Inhibitors of hepatitis C virus

ABSTRACT

The invention provides compounds of formula (I): 
                         
wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of replication of the hepatitis C virus. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat hepatitis C viral infections, and processes and intermediates useful for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.61/410,267, filed on Nov. 4, 2010, 61/444,046, filed on Feb. 17, 2011,and 61/492,267, filed on Jun. 1, 2011, the disclosures of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field Of The Invention

The invention is directed to compounds useful as inhibitors ofreplication of the hepatitis C virus (HCV). The invention is alsodirected to pharmaceutical compositions comprising such compounds,methods of using such compounds to treat HCV infection, and processesand intermediates useful for preparing such compounds.

2. State Of The Art

Recent estimates place the number of people infected with the hepatitisC virus (HCV) worldwide at more than 170 million, including 3 millionpeople in the United States. The infection rate is thought to be roughly4 to 5 times that of the human immunodeficiency virus (HIV). While insome individuals, the natural immune response is able to overcome thevirus, in the majority of cases, a chronic infection is established,leading to increased risk of developing cirrhosis of the liver andhepatocellular carcinomas. Infection with hepatitis C, therefore,presents a serious public health problem.

Prior to mid-2011, the accepted standard of care for HCV involved theuse of a pegylated interferon which is believed to act by boosting thebody's immune response, together with ribavirin. Unfortunately, thecourse of treatment is lengthy, typically 48 weeks, often accompanied byserious adverse side effects, including depression, flu-like symptoms,fatigue, and hemolytic anemia, and ineffective in up to 50% of patients.In mid-2011, two HCV protease inhibitors were approved in the UnitedStates to be used in combination with interferon and ribavirin. Althoughbetter cure rates have been reported, the course of therapy is stilllengthy and accompanied by undesirable side effects. Accordingly, thereremains a serious unmet need in HCV treatment.

The virus responsible for HCV infection has been identified as apositive-strand RNA virus belonging to the family Flaviviridae. The HCVgenome encodes a polyprotein that during the viral lifecycle is cleavedinto ten individual proteins, including both structural andnon-structural proteins. The six non-structural proteins, denoted asNS2, NS3, NS4A, NS4B, NS5A, and NS5B have been shown to be required forRNA replication. In particular, the NS5A protein appears to play asignificant role in viral replication, as well as in modulation of thephysiology of the host cell. Effects of NS5A on interferon signaling,regulation of cell growth and apoptosis have also been identified.(Macdonald et al., Journal of General Virology (2004), 85, 2485-2502.)Compounds which inhibit the function of the NS5A protein are expected toprovide a new approach to HCV therapy.

SUMMARY OF THE INVENTION

In one aspect, the invention provides novel compounds which inhibitreplication of the HCV virus.

Accordingly, the invention provides a compound of formula (I):

wherein:

R¹ is selected from C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, heteroaryl, andheterocycle;

wherein C₁₋₆alkyl is optionally substituted with —OR^(q), wherein R^(q)is hydrogen or C₁₋₃alkyl;

R² is selected from hydrogen and C₁₋₆alkyl;

R³ is selected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl,—C(O)OC₃₋₆cycloalkyl, —C(O)NR^(a)R^(b), —C(O)C₁₋₆alkyl,—C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl;

wherein

-   -   R^(a) and R^(b) are independently hydrogen or C₁₋₆alkyl;

R⁴ is —C(O)R⁵ or —S(O)₂R⁶;

R⁵ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,—C(R^(k)R^(d))NR^(e)R^(f), —NR^(g)R^(h), heteroaryl, heterocycle,—CH₂-heteroaryl, and phenyl;

wherein

-   -   C₁₋₆alkyl is optionally substituted with one or two substituents        independently selected from —OR^(c), —S(O)₂C₁₋₃alkyl,        —NHC(O)C₁₋₃alkyl, and —NHC(O)OC₁₋₃alkyl;    -   C₁₋₆alkoxy is optionally substituted with —OR^(d);    -   C₃₋₆cycloalkyl is optionally substituted with one, two, or three        substituents independently selected from C₁₋₃alkyl, NR^(j)R^(m),        —OR^(n), and halo;    -   any heterocycle is optionally substituted with one, two, or        three substituents independently selected from C₁₋₃alkyl, halo,        —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, —C(O)C₃₋₆cycloalkyl,        —C(O)NHC₁₋₆alkyl, —C(O)NHC₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl;        -   wherein any —C(O)C₁₋₆alkyl is optionally substituted with            —NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e), or heterocycle,        -   any —C(O)C₃₋₆cycloalkyl is optionally substituted with one            or two C₁₋₃alkyl, and        -   any —C(O)NHC₁₋₆alkyl is optionally substituted with —OR^(n)            or C₃₋₆cycloalkyl;    -   any heteroaryl is optionally substituted with C₁₋₆alkyl;    -   R^(c) is independently selected from hydrogen, C₁₋₆alkyl, and        phenyl;    -   R^(d) is independently hydrogen or C₁₋₆alkyl;    -   R^(e) is independently hydrogen or C₁₋₆alkyl;    -   R^(f) is independently selected from hydrogen, C₁₋₆alkyl,        —C(O)OC₁₋₆alkyl, and —C(O)C₁₋₆alkyl;    -   R^(n) is independently hydrogen or C₁₋₃alkyl;    -   R^(k) is independently selected from hydrogen, C₁₋₆alkyl,        C₃₋₆cycloalkyl, phenyl, and —CH₂OR⁶;    -   R^(g) is independently hydrogen or C₁₋₆alkyl;    -   R^(h) is independently selected from hydrogen, C₁₋₆alkyl,        C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl, wherein C₁₋₆alkyl is        optionally substituted with —OR^(d);    -   R^(j) is independently hydrogen or C₁₋₆alkyl;    -   R^(m) is independently selected from hydrogen, C₁₋₆alkyl,        —C(O)OC₁₋₆alkyl, and —C(O)C₁₋₆alkyl;

R⁶ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and a heteroarylring;

R⁷, R⁸, and R¹¹ are independently selected from halo, C₁₋₆alkyl,C₁₋₆alkoxy, —C(O)OR^(n), —CH₂NR^(a)R^(b), and —CN, wherein C₁₋₆alkyl andC₁₋₆alkoxy are optionally substituted with one, two, three, four, orfive halo, and wherein C₁₋₆alkoxy is optionally substituted with—OR^(d);

R⁹ is independently selected from C₁₋₆alkyl, —CH₂OR^(n),—C(O)NR^(n)R^(p), and C(O)OR^(n), wherein C₁₋₆alkyl is optionallysubstituted with —S(O)₂C₁₋₃alkyl or with —SC₁₋₃alkyl;

R^(p) is independently hydrogen or C₁₋₃alkyl;

R¹⁰ is selected from hydrogen, halo, C₁₋₆alkyl, —C(O)OR^(c),—C(O)NR^(a)R^(b), —CH₂NR^(a)R^(b), C₃₋₆cycloalkyl, and —CN;

W′, X′, Y′, and Z′ are independently carbon or nitrogen wherein anycarbon atom is bonded to hydrogen or to R¹¹, provided that at least twoof W′, X′, Y′, and Z′ are carbon;

W, X, Y, and Z are independently carbon or nitrogen wherein any carbonatom is bonded to hydrogen or to R⁷, provided that at least two of W, X,Y, and Z are carbon;

A_(m) is —NHC(O)— or —C(O)NH—;

Q, T, U, and V are independently carbon or nitrogen wherein any carbonatom is bonded to hydrogen or to R⁸, provided that at least two of Q, T,U, and V are carbon; and

a, b, c, and d are independently 0, 1, or 2;

or a pharmaceutically-acceptable salt or stereoisomer thereof.

As used hereinafter, the phrase “compound of formula (I)” means acompound of formula (I) or a pharmaceutically acceptable salt thereof;i.e., this phrase means a compound of formula (I) in free base form orin a pharmaceutically acceptable salt form unless otherwise indicated.

The invention also provides a pharmaceutical composition comprising acompound of the invention and a pharmaceutically-acceptable carrier. Inaddition, the invention provides a pharmaceutical composition comprisinga compound of the invention, a pharmaceutically-acceptable carrier andone or more other therapeutic agents useful for treating hepatitis Cviral infections.

The invention also provides a method of treating a hepatitis C viralinfection in a mammal, the method comprising administering to the mammala therapeutically effective amount of a compound or of a pharmaceuticalcomposition of the invention. In addition, the invention provides amethod of treating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound or a pharmaceuticalcomposition of the invention and one or more other therapeutic agentsuseful for treating hepatitis C viral infections. Further, the inventionprovides a method of inhibiting replication of the hepatitis C virus ina mammal, the method comprising administering a compound or apharmaceutical composition of the invention.

In separate and distinct aspects, the invention also provides syntheticprocesses and intermediates described herein, which are useful forpreparing compounds of the invention.

The invention also provides a compound of the invention as describedherein for use in medical therapy, as well as the use of a compound ofthe invention in the manufacture of a formulation or medicament fortreating a hepatitis C viral infection in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

Among other aspects, the invention provides inhibitors of HCVreplication of formula (I), pharmaceutically-acceptable salts thereof,and intermediates for the preparation thereof. The followingsubstituents and values are intended to provide representative examplesof various aspects of this invention. These representative values areintended to further define such aspects and are not intended to excludeother values or limit the scope of the invention.

In a specific aspect, R¹ is selected from C₁₋₆alkyl, phenyl,C₃₋₆cycloalkyl, heteroaryl, and heterocycle; wherein C₁₋₆alkyl isoptionally substituted with —OR^(q); wherein R^(q) is hydrogen orC₁₋₃alkyl.

In another specific aspect of the invention, R¹ is selected fromC₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl, heteroaryl, and heterocycle.

In another specific aspect, R¹ is selected from C₁₋₆alkyl, phenyl, andC₃₋₆cycloalkyl, wherein C₁₋₆alkyl is optionally substituted with—OR^(q); wherein R^(q) is hydrogen or C₁₋₃alkyl.

In another specific aspect, R¹ is selected from C₁₋₆alkyl and phenyl.

In a specific aspect, R¹ is C₁₋₃ alkyl.

In another specific aspect, R¹ is isopropyl.

In a specific aspect, R² is hydrogen or C₁₋₆alkyl.

In other specific aspects, R² is hydrogen or C₁₋₃alkyl; or R² ishydrogen.

In a specific aspect, R³ is selected from hydrogen, C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)OC₃₋₆cycloalkyl, —C(O)NR^(a)R^(b), —C(O)C₁₋₆alkyl,—C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl, wherein R^(a) and R^(b) areindependently hydrogen or C₁₋₆alkyl.

In another specific aspect, R³ is selected from hydrogen, C₁₋₆alkyl,—C(O)OC₁₋₆alkyl, —C(O)NR^(a)R^(b), —C(O)C₃₋₆cycloalkyl, and—S(O)₂C₁₋₃alkyl, wherein R^(a) and R^(b) are independently hydrogen orC₁₋₆alkyl.

In yet other specific aspects, R³ is selected from hydrogen, C₁₋₆alkyl,and —C(O)OC₁₋₆alkyl; and R³ is —C(O)OC₁₋₃alkyl.

In a specific aspect, R¹ is C₁₋₆alkyl, R² is hydrogen, and R³ is—C(O)OC₁₋₆alkyl.

In another specific aspect, R¹ is isopropyl, R² is hydrogen, and R³ is—C(O)OCH₃.

In yet other specific aspects, R¹ is phenyl and R² and R³ are eachC₁₋₃alkyl, or R¹ is phenyl and R² and R³ are each ethyl; or R¹ isphenyl, R² is hydrogen, and R³ is —C(O)OC₁₋₃alkyl.

In a specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is defined as in formula(I).

In another specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selected fromC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, —C(R^(k)R^(d))NR^(e)R^(f),—NR^(g)R^(h), heteroaryl, heterocycle, —CH₂-heteroaryl, and phenyl;wherein C₁₋₆alkyl is optionally substituted with —OR^(c) or—S(O)₂C₁₋₃alkyl; C₃₋₆cycloalkyl is optionally substituted with one ortwo C₁₋₃alkyl, or with NR^(j)R^(m) or —OR^(n); any heterocycle isoptionally substituted with one or two substituents selected fromC₁₋₃alkyl, halo, —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl optionally substitutedwith —NHC(O)OC₁₋₃alkyl, and —C(O)C₃₋₆cycloalkyl optionally substitutedwith one or two C₁₋₃alkyl; and any heteroaryl is optionally substitutedwith C₁₋₆alkyl, wherein R^(h) is selected from hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl, and R^(c), R^(k), R^(d), R^(e),R^(f), R^(g), R^(j), R^(m), and R^(n) are defined as in formula (I).

In another specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selected fromC₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, —C(R^(k)R^(d))NR^(e)R^(f),—NR^(g)R^(h), heteroaryl, heterocycle, and —CH₂-heteroaryl, wherein anyheteroaryl or heterocycle has five or six ring atoms; C₃₋₆cycloalkyl isoptionally substituted with one or two C₁₋₃alkyl; any heterocycle isoptionally substituted with one or two substituents selected fromC₁₋₃alkyl halo, —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl optionally substitutedwith —NHC(O)OC₁₋₃alkyl, and —C(O)C₃₋₆cycloalkyl optionally substitutedwith one or two C₁₋₃alkyl; R^(k), R^(d), R^(e), R^(g), and R^(h) areeach independently hydrogen or C₁₋₃alkyl; and R^(f) is selected fromhydrogen and —C(O)C₁₋₃alkyl.

In another specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selected fromC₃₋₄cycloalkyl, —CH₂NR^(e)R^(f), —NR^(g)R^(h), imidazolyl, pyrazolyl,pyrimidinyl, and pyrrolidinyl; wherein: C₃₋₄cycloalkyl is optionallysubstituted with one or two C₁₋₃alkyl; pyrrolidinyl is substituted withmethyl and a substituent selected from —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl,and —C(O)NHC₁₋₆alkyl, wherein—C(O)C₁₋₆alkyl is substituted with—NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e), or heterocycle.

In yet another specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selectedfrom, —O-tert-butyl, cyclopropyl, tert-butyl, —NHCH₃,2,2-dimethylcyclopropyl, pyrimidinyl, pyrazolyl, imidazolyl,—CH₂-pyrazolyl, 1-acetylpyrrolidinyl, 2-methylpyrrolidine-1-carboxylicacid methyl ester, 1-cyclopropyl-2-methylpyrrolidine,1--(2,2-dimethylcyclopropyl)-2-methylpyrrolidine, and[-2-methyl-1-(2-methyl-pyrrolidine-1-carbonyl)-propyl]-carbamic acidmethyl ester.

In yet another specific aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selectedfrom, —O-tert-butyl, cyclopropyl, tert-butyl, —NHCH₃,2,2-dimethylcyclopropyl, pyrimidinyl, pyrazolyl, imidazolyl,—CH₂-pyrazolyl, and 1-acetylpyrrolidinyl.

In another aspect, R⁴ is —C(O)R⁵ wherein R⁵ is a five- or six-memberedheteroaryl ring;

In yet another aspect R⁴ is —C(O)R⁵ wherein R⁵ is cyclopropyl or2,2-dimethylcyclopropyl.

In another aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selected from —NHCH₃,2,2-dimethylcyclopropyl,

In another aspect, R⁴ is —C(O)R⁵ wherein R⁵ is selected from —NHCH₃,2,2-dimethylcyclopropyl, and

In yet another aspect, R⁴ is —C(O)R⁵ wherein R⁵ is —NHCH₃

In a specific aspect, R⁴ is —S(O)₂R⁶ wherein R⁶ is selected fromC₁₋₆alkyl, C₃₋₆cycloalkyl, and heteroaryl.

In another specific aspect, R⁴ is —S(O)₂R⁶ wherein R⁶ is selected fromC₁₋₆alkyl, C₃₋₆cycloalkyl, and a five- or six-membered heteroaryl.

In another specific aspect, R⁴ is —S(O)₂R⁶ wherein R⁶ is C₁₋₆alkyl.

In yet another specific aspect, R⁴ is —S(O)₂R⁶ wherein R⁶ is methyl.

In a specific aspect, R⁷, R⁸, and R¹¹ are independently selected fromhalo,

C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OR^(n), —CH₂NR^(a)R^(b), and —CN, whereinC₁₋₆alkyl and C₁₋₆alkoxy are optionally substituted with one, two, orthree halo and wherein C₁₋₆alkoxy is optionally substituted with—OR^(d).

In another specific aspect, R⁷, R⁸, and R¹¹ are independently selectedfrom halo,

C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OR⁶, —CH₂NR^(a)R^(b), and —CN, whereinC₁₋₆alkyl and C₁₋₆alkoxy are optionally substituted with one, two, orthree halo

In a specific aspect, R⁷ is independently selected from halo, C₁₋₆alkyl,and C₁₋₆alkoxy wherein C₁₋₆alkyl and C₁₋₆alkoxy are optionallysubstituted with one, two, or three halo.

In another specific aspect, R⁷ is halo.

In yet another specific aspect, R⁷ is chloro or fluoro.

In still another specific aspect, R⁷ is selected from methyl, —CF₃,—OCH₃, —OCF₃, and fluoro.

In yet another specific aspect, R⁷ is selected from fluoro, chloro,—CF₃, and —OCF₃.

In a specific aspect, R⁹ is selected from C₁₋₆alkyl, —CH₂OR^(n),—C(O)NR^(n)R^(p), and C(O)OR^(n), wherein C₁₋₆alkyl is optionallysubstituted with —S(O)₂C₁₋₃alkyl or with —SC₁₋₃alkyl.

In another specific aspect, R⁹ is selected from C₁₋₆alkyl, —CH₂OR^(n),—C(O)NR^(n)R^(p), and C(O)OR^(n).

In another specific aspect, R⁹ is C₁₋₆alkyl or —CH₂OR^(n).

In another specific aspect, R⁹ is C₁₋₆alkyl.

In yet another specific aspect, R⁹ is methyl.

In a specific aspect, R¹⁰ is selected from hydrogen, halo, C₁₋₆alkyl,—C(O)OR^(c), —C(O)NR^(a)R^(b), —CH₂NR^(a)R^(b), C₃₋₆cycloalkyl, and —CN.

In a specific aspect, R¹⁰ is selected from hydrogen, halo, andC₁₋₆alkyl.

In other specific aspects, R¹⁰ is halo; or R¹⁰ is chloro.

In yet another specific aspect, R¹⁰ is hydrogen.

In a specific aspect W′, X′, Y′, and Z′ are each CH.

In a specific aspect, W, X, Y, and Z are independently carbon ornitrogen wherein any carbon atom is bonded to hydrogen or to R⁷,provided that at least two of W, X, Y, and Z are carbon.

In another specific aspect, W, X, Y, and Z are independently carbon ornitrogen wherein any carbon atom is bonded to hydrogen or R⁷, providedthat at least three of W, X, Y, and Z are carbon.

In another specific aspect, W, X, Y, and Z are each carbon and two of W,X, Y, and Z are CH and two of W, X, Y, and Z are bonded to R⁷.

In yet another specific aspect, W and Z are independently carbon bondedto R⁷ and X and Y are CH.

In a specific aspect, Q, T, U, and V are independently selected from CHand N.

In a specific aspect, Q, U, and V are each CH and T is N.

In a specific aspect, a is 1 or 2.

In another specific aspect, a is 1.

In another specific aspect a is 0.

In a specific aspect, b is 0.

In a specific aspect, c is 1 or 2.

In another specific aspect, c is 2.

In another specific aspect, c is 1.

In another specific aspect, c is 0.

In a specific aspect, d is 1.

In a specific aspect, d is 0.

In one aspect, the invention provides compounds of formula (I) disclosedin U.S. Provisional Application No. 61/492,267, filed on Jun. 1, 2011.

In another aspect, the invention provides compounds of formula (II):

wherein the variables of formula (II) are as defined herein.

In another aspect, the invention provides compounds of formula (III)

wherein the variables of formula (III) are as defined herein.

A particular group of compounds of formula (III) is a group wherein:

R¹ is selected from C₁₋₆alkyl, phenyl, and C₃₋₆cycloalkyl, whereinC₁₋₆alkyl is optionally substituted with —OR^(q);

R³ is selected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl,—C(O)NR^(a)R^(b), —C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl;

R⁵ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,—C(R^(k)R^(d))NR^(e)R^(f), —NR^(g)R^(h), heteroaryl, heterocycle, and—CH₂-heteroaryl;

wherein:

-   -   any heteroaryl or heterocycle has 5 or 6 ring atoms;    -   C₁₋₆alkyl is optionally substituted with one or two substituents        independently selected from —OR^(c), —NHC(O)C₁₋₃alkyl, and        —NHC(O)OC₁₋₃alkyl;    -   C₁₋₆alkoxy is optionally substituted with —OR^(d);    -   C₃₋₆cycloalkyl is optionally substituted with one or two        substituents independently selected from C₁₋₃alkyl and halo;    -   any heterocycle is optionally substituted with one, two, or        three substituents independently selected from C₁₋₃alkyl, halo,        —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, —C(O)C₃₋₆cycloalkyl,        —C(O)NHC₁₋₆alkyl, and —C(O)NHC₃₋₆cycloalkyl;        -   wherein any —C(O)C₁₋₆alkyl is optionally substituted with            —NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e), or heterocycle,        -   any —C(O)C₃₋₆cycloalkyl is optionally substituted with one            or two C₁₋₃alkyl, and        -   any —C(O)NHC₁₋₆alkyl is optionally substituted with —OR^(n)            or C₃₋₆cycloalkyl;    -   any heteroaryl is optionally substituted with C₁₋₃alkyl;    -   R^(k), R^(d), R^(e), R^(g), and R^(h) are each independently        hydrogen or C₁₋₃alkyl;    -   R^(f) is selected from hydrogen and —C(O)C₁₋₃alkyl;

R⁷ is selected from halo, C₁₋₃alkyl, and C₁₋₃alkoxy wherein C₁₋₆alkyland C₁₋₆alkoxy are optionally substituted with one, two, or three halo;

R⁹ is C₁₋₃alkyl;

a is 1 or 2; and

c is 1 or 2; and all other variables are as defined in formula (I).

Another group of compounds of formula (III) is a group wherein:

R⁵ is selected from C₃₋₄cycloalkyl, —CH₂NR^(e)R^(f), —NR^(g)R^(h),imidazolyl, pyrazolyl, pyrimidinyl, and pyrrolidinyl;

wherein:

-   -   C₃₋₄cycloalkyl is optionally substituted with one or two        C₁₋₃alkyl; pyrrolidinyl is substituted with methyl and a        substituent selected from —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl,        —C(O)NHC₁₋₆alkyl, wherein        -   —C(O)C₁₋₆alkyl is substituted with —NHC(O)OC₁₋₃alkyl,            —OR^(n), —NR^(d)R^(e), or heterocycle;    -   wherein R^(e), R^(g), and R^(h) are each independently hydrogen        or C₁₋₃alkyl; and

R^(f) is selected from hydrogen and —C(O)C₁₋₃alkyl.

Yet another group of compounds of formula (III) is a group wherein:

R¹ is isopropyl, R² is hydrogen; R³ is —C(O)OCH₃;

R⁷ is selected from fluoro, chloro, —CF₃, and —OCF₃, R⁹ is methyl; and

R⁵ is selected from —NHCH₃,2,2-dimethylcyclopropyl, and

In another aspect, the invention additionally provides compounds offormula (IV):

wherein the variables of formula (IV) are as defined herein.

In still another aspect, the invention provides compounds of formula(V):

wherein the variables are as defined herein.

In one aspect, the invention provides the compounds of Examples 1-77 andTables 1-34 below.

In yet another aspect, the invention provides a compound selected fromthe compounds depicted below

and pharmaceutically-acceptable salts thereof.

In a still further aspect, the invention provides a compound selectedfrom the following compounds

and pharmaceutically-acceptable salts thereof.

The chemical naming convention used herein is illustrated for thecompound of Example 1:

which is{(S)-1-[(S)-2-(4-{4′-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester according to the IUPAC conventions as implemented inAutoNom software, (MDL Information Systems, GmbH, Frankfurt, Germany).

The compounds of the invention contain one or more chiral centers andtherefore, such compounds (and intermediates thereof) can exist asracemic mixtures; pure stereoisomers (i.e., enantiomers ordiastereomers); stereoisomer-enriched mixtures and the like. Chiralcompounds shown or named herein without a defined stereochemistry at achiral center are intended to include any or all possible stereoisomervariations at the undefined stereocenter unless otherwise indicated. Thedepiction or naming of a particular stereoisomer means the indicatedstereocenter has the designated stereochemistry with the understandingthat minor amounts of other stereoisomers may also be present unlessotherwise indicated, provided that the utility of the depicted or namedcompound is not eliminated by the presence of another stereoisomer.

Compounds of formula (I) also contain several basic groups (e.g., aminogroups) and therefore, such compounds can exist as the free base or invarious salt forms, such a mono-protonated salt form, a di-protonatedsalt form, a tri-protonated salt form, or mixtures thereof. All suchforms are included within the scope of this invention, unless otherwiseindicated.

This invention also includes isotopically-labeled compounds of formula(I), i.e., compounds of formula (I) where an atom has been replaced orenriched with an atom having the same atomic number but an atomic massdifferent from the atomic mass that predominates in nature. Examples ofisotopes that may be incorporated into a compound of formula (I)include, but are not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, 15O,¹⁷O, ¹⁸O, ³⁵S, ³⁶Cl, and ¹⁸F. Of particular interest are compounds offormula (I) enriched in tritium or carbon-14, which compounds can beused, for example, in tissue distribution studies. Also of particularinterest are compounds of formula (I) enriched in deuterium especiallyat a site of metabolism, which compounds are expected to have greatermetabolic stability. Additionally of particular interest are compoundsof formula (I) enriched in a positron emitting isotope, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, which compounds can be used, for example, in PositronEmission Tomography (PET) studies.

Definitions

When describing this invention including its various aspects andembodiments, the following terms have the following meanings, unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched or combinations thereof. Unless otherwisedefined, such alkyl groups typically contain from 1 to 10 carbon atoms.Representative alkyl groups include, by way of example, methyl (Me),ethyl (Et), n-propyl (n-Pr) or (nPr), isopropyl (i-Pr) or (iPr), n-butyl(n-Bu) or (nBu), sec-butyl, isobutyl, tert-butyl (t-Bu) or (tBu),n-pentyl, n-hexyl, 2,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl,2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like

When a specific number of carbon atoms are intended for a particularterm, the number of carbon atoms is shown preceding the term. Forexample, the term “C₁₋₃ alkyl” means an alkyl group having from 1 to 3carbon atoms wherein the carbon atoms are in any chemically-acceptableconfiguration, including linear or branched configurations.

The term “alkoxy” means the monovalent group —O-alkyl, where alkyl isdefined as above. Representative alkoxy groups include, by way ofexample, methoxy, ethoxy, propoxy, butoxy, and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic groupwhich may be monocyclic or multicyclic. Unless otherwise defined, suchcycloalkyl groups typically contain from 3 to 10 carbon atoms.Representative cycloalkyl groups include, by way of example, cyclopropyl(cPr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,adamantyl, and the like.

The term “heterocycle”, “heterocyclic”, or “heterocyclic ring” means amonovalent saturated or partially unsaturated cyclic non-aromatic group,having from 3 to 10 total ring atoms, wherein the ring contains from 2to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selected fromnitrogen, oxygen, and sulfur. Heterocyclic groups may be monocyclic ormulticyclic (i.e., fused or bridged). Representative heterocyclic groupsinclude, by way of example, pyrrolidinyl, piperidinyl, piperazinyl,imidazolidinyl, morpholinyl, thiomorpholyl, indolin-3-yl,2-imidazolinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl,7-azanorbornanyl, nortropanyl, and the like, where the point ofattachment is at any available carbon or nitrogen ring atom. Where thecontext makes the point of attachment of the heterocyclic group evident,such groups may alternatively be referred to as a non-valent species,i.e. pyrrolidine, piperidine, piperazine, imidazole, etc.

The term “heteroaryl” or “heteroaryl ring” means a monovalent aromaticgroup having from 5 to 10 total ring atoms, wherein the ring containsfrom 1 to 9 carbon ring atoms and from 1 to 4 ring heteroatoms selectedfrom nitrogen, oxygen, and sulfur. Heteroaryl groups may be monocyclicor multicyclic. Representative heteroaryl groups include, by way ofexample, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, triazinyl, thienyl, pyridyl (or, equivalently, pyridinyl),pyrimidyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, and the like, where the point ofattachment is at any available carbon or nitrogen ring atom. Where thecontext makes the point of attachment of the heteroaryl group evident,such groups may alternatively be referred to as a non-valent species,i.e. pyrrole, isoxazole, isothiazole, pyrazole, imidazole, etc.

The term “halo” means fluoro, chloro, bromo or iodo.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.

The term “treatment” as used herein means the treatment of a disease,disorder, or medical condition in a patient (such as hepatitis C viralinfection), such as a mammal (particularly a human) which includes oneor more of the following:

(a) preventing the disease, disorder, or medical condition fromoccurring, i.e., preventing the reoccurrence of the disease or medicalcondition or prophylactic treatment of a patient that is pre-disposed tothe disease or medical condition;

(b) ameliorating the disease, disorder, or medical condition, i.e.,eliminating or causing regression of the disease, disorder, or medicalcondition in a patient, including counteracting the effects of othertherapeutic agents;

(c) suppressing the disease, disorder, or medical condition, i.e.,slowing or arresting the development of the disease, disorder, ormedical condition in a patient; or

(d) alleviating the symptoms of the disease, disorder, or medicalcondition in a patient.

The term “pharmaceutically acceptable salt” means a salt that isacceptable for administration to a patient or a mammal, such as a human(e.g., salts having acceptable mammalian safety for a given dosageregime). Representative pharmaceutically acceptable salts include saltsof acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic,glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic,lactobionic, maleic, malic, mandelic, methanesulfonic, mucic,naphthalenesulfonic, naphthalene-1,5-disulfonic,naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand xinafoic acid, and the like.

The term “salt thereof” means a compound formed when the hydrogen of anacid is replaced by a cation, such as a metal cation or an organiccation and the like. For example, the cation can be a protonated form ofa compound of formula (I), i.e. a form where one or more amino groupshave been protonated by an acid. Typically, the salt is apharmaceutically acceptable salt, although this is not required forsalts of intermediate compounds that are not intended for administrationto a patient.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino nitrogen. Representativeamino-protecting groups include, but are not limited to, formyl; acylgroups, for example alkanoyl groups, such as acetyl andtri-fluoroacetyl; alkoxycarbonyl groups, such as tert butoxycarbonyl(Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl(Bn), trityl (Tr), and 1,1-di-(4′-methoxyphenyl)methyl; silyl groups,such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS),[2-(trimethylsilyl)ethoxy]methyl (SEM); and the like. Numerousprotecting groups, and their introduction and removal, are described inT. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,Third Edition, Wiley, New York

General Synthetic Procedures

Compounds of this invention, and intermediates thereof, can be preparedaccording to the following general methods and procedures usingcommercially-available or routinely-prepared starting materials andreagents. The substituents and variables (e.g., R¹, R², R³, R⁴, etc.)used in the following schemes have the same meanings as those definedelsewhere herein unless otherwise indicated. Additionally, compoundshaving an acidic or basic atom or functional group may be used or may beproduced as a salt unless otherwise indicated (in some cases, the use ofa salt in a particular reaction will require conversion of the salt to anon-salt form, e.g., a free base, using routine procedures beforeconducting the reaction).

Although a particular embodiment of the present invention may be shownor described in the following procedures, those skilled in the art willrecognize that other embodiments or aspects of the present invention canalso be prepared using such procedures or by using other methods,reagents, and starting materials know to those skilled in the art. Inparticular, it will be appreciated that compounds of the invention maybe prepared by a variety of process routes in which reactants arecombined in different orders to provide different intermediates en routeto producing final products.

In one exemplary method of synthesis, compounds of formula (1-3) inwhich A_(m) is defined as —NHC(O)— are prepared as shown in Scheme 1:

where R^(4a) is an amino-protecting group Pg or R^(4a) is R⁴ as definedin formula (I), and G represents the group G₁

where R¹, R², and R³ are defined as in formula (I), or as anamino-protecting group Pg. Aniline intermediate 1-1 is reacted withcarboxylic acid 1-2 according to typical amide bond formation conditionsto provide a compound of formula 1-3 In some instances, the carboxylicacid 1-2 is first converted to an acid chloride and then reacted withaniline intermediate 1-1 to provide a compound of formula 1-3. As shownin the examples below, the amide bond formation reaction may utilizecoupling agents, such asN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yOuroniumhexafluorophosphate (HATU), or as 1,3 dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), orbenzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate(PyBop), optionally combined with 1-hydroxy-7-azabenzotriazole (HOAt).Preferably, the process of Scheme 1 is used to prepare compounds offormula 1-3 in which R⁷ is absent (a is 0) or R⁷ is an electron richsubstituent such as an unsubstituted-alkyl or unsubstituted-alkoxy, andthe reaction is performed in the presence of coupling agents EDC andHOAt at a temperature of about 50 to about 60° C. Preferably, only oneof G and R^(4a) is a protecting group, or, if two protecting groups arepresent, groups removable under different conditions are used.

When the variable R^(4a) is defined as R⁴ and the variable G is definedas G₁, then the product 1-3 of the reaction of Scheme 1 is a finalcompound of formula (I).

Alternatively, when R^(4a) is defined as R⁴ and G is defined asprotecting group Pg, for example Boc, the product 1-3 of the reaction ofScheme 1 is a protected intermediate which is then deprotected, forexample, by treatment with an acid, and reacted with a reagent X-G₁,where X is a halogen leaving group, or with a carboxylic acid of formulaHO-G₁, the latter under amide bond formation conditions as describedabove, to provide the desired product.

In another exemplary method of synthesis, compounds of formulas 2-2 and2-3 are prepared as shown in Scheme 2:

When G represents G₁ in intermediate 2-1, then the reaction of Scheme 2,directly provides compounds of the invention. To prepare a compound offormula 2-2 where R⁴ is defined as —C(O)R⁵, intermediate 2-1 is reactedwith an acid chloride (reaction (i)) or, where R⁵ is defined as—NR^(g)R^(h), with an isocyanate (reaction (iii)) in the presence ofbase. Alternatively, intermediate 2-1 is reacted with a carboxylic acid(reaction (ii)) under amide bond formation conditions to prepare acompound of formula 2-2. Similarly, to prepare a compound of formula 2-3where R⁴ is defined as —S(O)₂R⁶, intermediate 2-1 is typically reactedwith a sulfonyl chloride in the presence of base (reaction (iv)).

As described above, when G represents a protecting group a subsequentdeprotection step, and coupling with an intermediate X-G₁ or HO-G₁provides the final product.

The intermediates of the above Schemes may be prepared by conventionalsynthetic reactions. For example, the biaryl aniline intermediate 1-1may be prepared by the Suzuki coupling reaction in the presence of apalladium catalyst (Miyaura and Suzuki, Chem. Rev. 1995, 95, 2457-2483).As shown in Scheme 3 below, either coupling partner may bear theboronate moiety. Alternatively, a boronic acid reagent may be used inplace of a boronate reagent, such as the pinacol boronate depictedbelow.

An exemplary process for the preparation of intermediate 1-2 in whichR^(4a) represents Pg (compound 1-2″) or R^(4a) represents, for example,—C(O)R⁵ (compound 1-2′) is shown in Scheme 4.

The reaction of a piperazine with a fluorobenzoic ester orfluoronicotinic ester 4-1, typically a methyl or ethyl ester, may beperformed in dimethylsulfoxide in the presence of potassium carbonate atelevated temperature, typically about 100° C. to about 130° C. Theresulting intermediate 4-2 is subsequently hydrolyzed to provideprotected intermediate 1-2″. To prepare intermediate 1-2′, protectedintermediate 1-2″, where preferably the protecting group is Boc, can bedeprotected and then reacted with an acid chloride, carboxylic acid, orisocyanate as in Scheme 2 to provide intermediate 1-2′.

An alternative process for the preparation of intermediate 1-2 in whichT represents nitrogen and R^(4a) represents Pg (compound 1-2a″) orR^(4a) represents —C(O)R⁵ (compound 1-2a′) is shown in Scheme 5.

The reaction of a fluoronicotinic acid 5-1 with the protected piperazine5-2 to provide intermediate 1-2a″ is typically performed usingisopropylmagnesium chloride at a temperature below about −20° C.

To prepare intermediate 1-2a′, protected intermediate 1-2a″, wherepreferably the protecting group is Boc, can be deprotected andesterified by reaction with sulfuric acid in methanol to provide anester intermediate 5-3, which is reacted with an acid chloride,carboxylic acid, or isocyanate as in Scheme 2 and subsequentlyhydrolyzed to provide intermediate 1-2a′.

Intermediate 2-1 where G represents G₁ may be prepared by the process ofScheme 1 where the variable R^(4a) is defined as protecting group Pg. Inthis instance, formula 1-3 describes a protected intermediate, which isdeprotected to provide intermediate 2-1.

An alternative process for the preparation of intermediate 2-1 in whichT represents nitrogen (compound 2-1a) is shown in Scheme 6.

In a first step, biphenyl aniline 1-1 is reacted with a fluoropyridinecarbonyl chloride 6-1 in the presence of base to provide fluorointermediate 6-2, which is reacted with an excess of protectedpiperidine 5-2 to provide protected intermediate 6-3. The reactiontypically is performed in the presence of base with heating to atemperature of about 80° C. to about 120° C. for a period of about 4 toabout 48 hours. Finally, intermediate 6-3 is deprotected, for example,by treatment with hydrochloric acid in an organic solvent to provideintermediate 2-1a as the HCl salt.

Yet another alternative process for the preparation of intermediate 2-1autilizes a Suzuki coupling reaction of the boronate reagent 3-2 withintermediate 7-1, followed by a deprotection step, under conditionsdescribed above, as shown in Scheme 7.

If protected intermediate 7-1 were replaced by an intermediate 7-1′bearing the substituent R⁴

then the Suzuki coupling of the boronate 3-2 in the first step of Scheme7 would directly provide a final compound of the invention.

In the Suzuki coupling reaction of Scheme 7, alternatively, the oppositecoupling partner could bear the boronate moiety, as shown in Scheme 3.

The bromo intermediate 7-1 may be prepared, for example, by amidecoupling of arylamine 8-1 with a fluoropyridine carbonyl chloride 6-1,followed by reaction with a protected piperazine 5-2 as shown in Scheme8.

Alternatively, intermediate 7-1 may be prepared by the reaction of 8-1with the carboxylic acid intermediate 1-2″ as given in Scheme 9.

Intermediates 3-1 and 3-2 used in the Suzuki reaction of Scheme 3 may beprepared, for example, as shown in Schemes 10 and 11.

Reagent 10-1, where X represents bromo or chloro is reacted with aprotected proline carboxylic acid 10-2 to provide intermediate 10-3which is converted to intermediate 3-1″, where the variable G representsa protecting group, in the presence of an excess of ammonium acetate.The ring closure reaction typically is performed at a temperaturebetween about 100° C. and about 120° C. for a period of about 4 to about24 hours. To provide compound 3-1′ where the variable G represents G₁,intermediate 3-1″ is typically deprotected to provide intermediate 10-4,which is then coupled with a reagent HO-G₁ to provide compound 3-1′.

Finally, to provide boronate intermediate 3-2, intermediate 3-1 isreacted with 11-1 in the presence of a palladium catalyst as shown inScheme 11.

For the preparation of intermediate 2-1a in Scheme 7, boronateintermediate 3-2 may be prepared in situ according to the process ofScheme 11 and then reacted with intermediate 7-1 to provide intermediate6-3 in a single pot process.

Compounds of Formula 12-3 in which the variable A_(m) is defined as—C(O)NH— are prepared by processes analogous to those described above.One exemplary process for the preparation of compounds of Formula 12-3is shown in Scheme 12.

The acid 12-1 and aniline or aminopyridine 12-2 are reacted under amidebond formation conditions. As above, when the variable R^(4a) representsR⁴ and the variable G represents G₁, then the reaction of Scheme 12directly provides final compounds of formula (I).

Alternatively, when R^(4a) represents R⁴ and G represents protectinggroup Pg, for example Boc, the reaction provides a protectedintermediate of formula 12-3 which is then deprotected and reacted witha reagent X-G₁, where X is a halogen leaving group, or with a carboxylicacid of formula HO-G₁, to provide the desired product.

In yet another alternative route, a compound of formula 12-3 in which Gis defined as G₁ and R^(4a) is a protecting group Pg, provides a usefulintermediate, which is deprotected and reacted, for example, with anacid chloride, carboxylic acid, or isocyanate, as in Scheme 2 to providefinal compounds of formula (I).

The intermediates of Scheme 12 may be prepared by conventional syntheticreactions. For example, the biaryl acid intermediate 12-1 may beprepared by the Suzuki coupling reaction of Scheme 13

A useful process for the preparation of the aminopyridine intermediate12-2 of Scheme 12 utilizes a nitro substituted-chloropyridine orchlorophenyl 14-1 which is reacted with a protected piperazine 5-2 toprovide a protected intermediate 14-2 as shown in Scheme 14.

Reduction of the nitro group to the amine provides intermediate 12-2″where R^(4a) represents a protecting group. Deprotection of compound12-2″ and reaction, for example, with an acid chloride, carboxylic acid,or isocyanate, as in schemes above provides intermediate 12-2′, in whichR^(4a) represents R⁴.

It will be understood by those of skill in the art, that other compoundsof the invention having heterocyclic rings in place of the phenyl ringsof the structures in the above schemes may be prepared by similarmethods starting with appropriate starting materials. Details regardingspecific reaction conditions and other procedures for preparingrepresentative compounds of the invention or intermediates thereto aredescribed in the examples below.

It will further be understood, this disclosure encompasses compounds offormula (I) when prepared by synthetic processes such as those describedabove and below or by metabolic processes including those occurring invivo in human or animal body or in vitro.

Pharmaceutical Compositions

The compounds of the invention and pharmaceutically-acceptable saltsthereof are typically used in the form of a pharmaceutical compositionor formulation. Such pharmaceutical compositions may be administered toa patient by any acceptable route of administration including, but notlimited to, oral, rectal, vaginal, nasal, inhaled, topical (includingtransdermal) and parenteral modes of administration.

Accordingly, in one of its compositions aspects, the invention isdirected to a pharmaceutical composition comprising apharmaceutically-acceptable carrier or excipient and a compound offormula (I), where, as defined above, “compound of formula (I)” means acompound of formula (I) or a pharmaceutically-acceptable salt thereof.Optionally, such pharmaceutical compositions may contain othertherapeutic and/or formulating agents if desired. When discussingcompositions and uses thereof, the “compound of the invention” may alsobe referred to herein as the “active agent”. As used herein, the term“compound of the invention” is intended to include all compoundsencompassed by formula (I) as well as the species embodied in formulas(II), (III), (IV), and (V), and pharmaceutically-acceptable saltsthereof.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the present invention.Those skilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amount,i.e., bulk compositions, or less than a therapeutically effectiveamount, i.e., individual unit doses designed for multiple administrationto achieve a therapeutically effective amount.

Typically, such pharmaceutical compositions will contain from about 0.1to about 95% by weight of the active agent; preferably, from about 5 toabout 70% by weight; and more preferably from about 10 to about 60% byweight of the active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the carriers or excipients used inthe pharmaceutical compositions of this invention arecommercially-available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20th Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7th Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with apharmaceutically-acceptable carrier and one or more optionalingredients. The resulting uniformly blended mixture can then be shapedor loaded into tablets, capsules, pills and the like using conventionalprocedures and equipment.

The pharmaceutical compositions of the invention are preferably packagedin a unit dosage form. The term “unit dosage form” refers to aphysically discrete unit suitable for dosing a patient, i.e., each unitcontaining a predetermined quantity of active agent calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like, or unit packages suitablefor parenteral administration.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for oral administration. Suitable pharmaceutical compositionsfor oral administration may be in the form of capsules, tablets, pills,lozenges, cachets, dragees, powders, granules; or as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water orwater-in-oil liquid emulsion; or as an elixir or syrup; and the like;each containing a predetermined amount of a compound of the presentinvention as an active ingredient.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise the active agent and one ormore pharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate. Optionally or alternatively, such solid dosageforms may also comprise: fillers or extenders, such as starches,microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and/orsilicic acid; binders, such as carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, suchas glycerol; disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and/or sodium carbonate; solution retarding agents, such as paraffin;absorption accelerators, such as quaternary ammonium compounds; wettingagents, such as cetyl alcohol and/or glycerol monostearate; absorbents,such as kaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically-acceptable antioxidants include: water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents, such ascitric acid, ethylenediamine tetraacetic acid, sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acidmethacrylic acid estercopolymers, cellulose acetate trimellitate, carboxymethyl ethylcellulose, hydroxypropyl methyl cellulose acetate succinate, and thelike.

Pharmaceutical compositions of the invention may also be formulated toprovide slow or controlled release of the active agent using, by way ofexample, hydroxypropyl methyl cellulose in varying proportions; or otherpolymer matrices, liposomes and/or microspheres. In addition, thepharmaceutical compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active agent can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (esp., cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Suspensions, inaddition to the active ingredient, may contain suspending agents suchas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The compounds of this invention can also be administered parenterally(e.g. by intravenous, subcutaneous, intramuscular or intraperitonealinjection). For parenteral administration, the active agent is typicallyadmixed with a suitable vehicle for parenteral administration including,by way of example, sterile aqueous solutions, saline, low molecularweight alcohols such as propylene glycol, polyethylene glycol, vegetableoils, gelatin, fatty acid esters such as ethyl oleate, and the like.Parenteral formulations may also contain one or more anti-oxidants,solubilizers, stabilizers, preservatives, wetting agents, emulsifiers,buffering agents, or dispersing agents. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat.

Alternatively, the pharmaceutical compositions of the invention areformulated for administration by inhalation. Suitable pharmaceuticalcompositions for administration by inhalation will typically be in theform of an aerosol or a powder. Such compositions are generallyadministered using well-known delivery devices, such as a metered-doseinhaler, a dry powder inhaler, a nebulizer or a similar delivery device.

When administered by inhalation using a pressurized container, thepharmaceutical compositions of the invention will typically comprise theactive ingredient and a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas.Additionally, the pharmaceutical composition may be in the form of acapsule or cartridge (made, for example, from gelatin) comprising acompound of the invention and a powder suitable for use in a powderinhaler. Suitable powder bases include, by way of example, lactose orstarch.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example,the active agent can be admixed with permeation enhancers, such aspropylene glycol, polyethylene glycol monolaurate, azacycloalkan-2-onesand the like, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

Utility

The compounds of the invention have been shown to inhibit viralreplication in HCV replicon assays and therefore are expected to beuseful for the treatment of hepatitis C viral infections.

In one aspect, therefore, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal (e.g., a human), themethod comprising administering to the mammal atherapeutically-effective amount of a compound of the invention or of apharmaceutical composition comprising a pharmaceutically-acceptablecarrier and a compound of the invention.

The invention further provides a method of treating hepatitis C viralinfections in a mammal (e.g., a human), the method comprisingadministering to the mammal a therapeutically-effective amount ofcompound of the invention or of a pharmaceutical composition comprisinga pharmaceutically-acceptable carrier and a compound of the invention.

The compounds of the invention may inhibit viral replication byinhibiting the function of the NS5A protein encoded by the HCV genome.In one aspect, therefore, the invention provides a method of inhibitingthe NS5A protein of HCV in a mammal, the method comprising administeringto the mammal, a compound or a composition of the invention.

When used to treat HCV infections, the compounds of the invention willtypically be administered orally in a single daily dose or in multipledoses per day, although other forms of administration may be used. Theamount of active agent administered per dose or the total amountadministered per day will typically be determined by a physician, in thelight of the relevant circumstances, including the condition to betreated, the chosen route of administration, the actual compoundadministered and its relative activity, the age, weight, and response ofthe individual patient, the severity of the patient's symptoms, and thelike.

Suitable doses for treating HCV infections will range from about 1 toabout 2000 mg/day of active agent, including from about 5 to about 200mg/day and from about 10 to about 130 mg per day of active agent for anaverage 70 kg human.

Combination Therapy

Compounds of the invention may also be used in combination with one ormore agents which act by the same mechanism or by different mechanismsto effect treatment of HCV. Useful classes of agents for combinationtherapy include, but are not limited to, HCV NS3 protease inhibitors,HCV NS5B nucleoside and non-nucleoside polymerase inhibitors, helicaseinhibitors, NS4B protein inhibitors, HCV viral entry inhibitors,cyclophyllin inhibitors, toll-like receptor agonists, inhibitors of heatshock proteins, interfering RNA, antisense RNA, HCV internal ribosomeentry site (IRES) inhibitors, thiazolides, nucleoside analogs such asribavirin and related compounds, interferons and other immunomodulatoryagents, inosine 5′-monophosphate dehydrogenase (IMPDH) inhibitors, andother NS5A protein inhibitors. Agents which act to inhibit HCVreplication by any other mechanism may also be used in combination withthe present compounds.

HCV NS3 protease inhibitors which may be used in combination therapyinclude, but are not limited to, telaprevir (VX-950), boceprevir(SCH-503034), TMC-435, narlaprevir (SCH-900518), vaniprevir (MK-7009),danoprevir (ITMN-191, R-7227), BI-201335, ABT-450, BMS-650032, GS-9256,ACH-1625, ACH-2684, BMS-605339, VX-985, PHX-1766, BMS-791325, andIDX-320.

Examples of HCV NS5B nucleoside polymerase inhibitors include, but arenot limited to, RG7128, IDX-184, PSI-7977, PSI-7851, PSI-938, INX-189(INX-08189), RG7348, MK-0608, TMC-649128, and HCV-796, while,non-nucleoside HCV NS5B polymerase inhibitors, include but are notlimited to, filibuvir (PF-8685540), tegobuvir (GS-9190), VX-222, VX-759,ANA-598 (setrobuvir), ABT-072, ABT-333, BI-207127, BMS-791325, MK-3281,IDX-37, and BMS-824393.

A wide variety of interferons and pegylated interferons, includingalpha, beta, omega, and gamma interferons, having antiviral,antiproliferative or immunomodulatory effects, can be combined with thepresent compounds. Representative examples include, but are not limitedto, Intron® A (interferon-alpha2b), Actimmune® (interferon-gamma-1b),Alferon N, Advaferon®, Roferon-A (interferon alpha-2a) Peglntron®(peginterferon-alpha 2b), Alfaferone, Pegasys® (peginterferon alpha-2a),Alfanative (interferon alpha), Zalbin™ (albinterferon alpha-2b),Infergon® (interferon alfacon-1), Omega DUROS® (omega interferon),Locteron™ (interferon alpha), PEG-rIL-29 (pegylated interferon lambda),and Rebif® (interferon beta-1a).

Nucleoside analog antiviral agents include, but are not limited to,ribavirin (Copegus®, Rebetol®, Virazole®) and Viramidine (taribavirin).Interferons and ribavirin are also provided in in the form of kits whichinclude, for example, but are not limited to, Rebetron® (interferonalpha-2b/ribavirin) and Pegetron® (Peginterferon alpha-2b/ribavirin)

Useful compounds acting by other mechanisms include, but are not limitedto: cyclophilin inhibitors, such as DEB-025, SCY-635, NIM-811, andcyclosporine and derivatives; toll-like receptor agonists, such asresiquimod, IMO-2125, and ANA-773, HCV viral entry inhibitors, such ascivacir, thiazolides, such as nitazoxanide, and broad-spectrum viralinhibitors, such as, inosine-5′-monophosphate dehydrogenase (IMPDH)inhibitors.

In addition, compounds of the invention may be combined with an NS5Ainhibitor, for example, BMS-790052, AZD-7295, PPI-461, PPI-1301,GS-5885, or GSK2336805.

In another aspect, therefore, the invention provides a therapeuticcombination for use in the treatment of hepatitis C viral infections,the combination comprising a compound of the invention and one or moreother therapeutic agents useful for treating HCV. For example, theinvention provides a combination comprising a compound of the inventionand one or more agents selected from HCV NS3 protease inhibitors, HCVNS5B nucleoside and non-nucleoside polymerase inhibitors, interferonsand pegylated interferons, and ribavirin and related nucleoside analogs.Also provided, therefore, is a pharmaceutical composition comprising acompound of the invention and one or more other therapeutic agentsuseful for treating HCV.

Further, in a method aspect, the invention provides a method of treatinga hepatitis C viral infection in a mammal, the method comprisingadministering to the mammal a compound of the invention and one or moreother therapeutic agents useful for treating HCV.

In another method aspect, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal, the method comprisingadministering to the mammal a compound of the invention and one or moreother therapeutic agents useful for inhibiting replication of thehepatitis C virus.

For example, in one method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention, aninterferon or pegylated interferon, and ribavirin.

In another exemplary method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention, aninterferon or pegylated interferon, ribavirin, and an HCV NS3 proteaseinhibitor.

In still another method aspect, the invention provides a method oftreating a hepatitis C viral infection in a mammal, the methodcomprising administering to the mammal a compound of the invention,ribavirin, and an HCV NS3 protease inhibitor.

Still other combination therapies, include, for example, a compound ofthe invention, an HCV NS3 protease inhibitor, an HCV NS5B nucleosidepolymerase inhibitor, and an HCV NS5B non-nucleoside polymeraseinhibitor; and a compound of the invention, an HCV NS5B nucleosidepolymerase inhibitor, and an HCV NS5B non-nucleoside polymeraseinhibitor.

In another method aspect, the invention provides a method of inhibitingreplication of the hepatitis C virus in a mammal, using a compound ofthe invention in combination with other agents, as described above.

When used in combination therapy, the agents may be formulated in asingle pharmaceutical composition, as disclosed above, or the agents maybe provided in separate compositions that are administeredsimultaneously or at separate times, by the same or by different routesof administration. When administered separately, the agents areadministered sufficiently close in time so as to provide a desiredtherapeutic effect.

Such compositions can be packaged separately or may be packaged togetheras a kit. The two or more therapeutic agents in the kit may beadministered by the same route of administration or by different routesof administration.

Finally, the compounds of the invention may also find utility asresearch tools, for example, for discovering new HCV NS5A proteininhibitors or explicating mechanisms of HCV replication.

Compounds of the invention have been demonstrated to be potentinhibitors of HCV replication in HCV replicon assays, as described inthe following examples.

EXAMPLES

The following synthetic and biological examples are offered toillustrate the invention, and are not to be construed in any way aslimiting the scope of the invention. In the examples below, thefollowing abbreviations have the following meanings unless otherwiseindicated. Abbreviations not defined below have their generally acceptedmeanings.

-   -   ACN=acetonitrile    -   DCM=dichloromethane    -   DMA=N,N-dimethylacetamide    -   DMF=N,N-dimethylformamide    -   DMSO=dimethyl sulfoxide    -   EDC=N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride    -   EtOAc=ethyl acetate    -   h=hour(s)    -   HATU=N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   HCTU=2-(6-chloro-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium        hexafluorophosphate    -   HOAt=1-hydroxy-7-azabenzotriazole    -   min=minute(s)    -   Pd(dppf)Cl₂=dichloro(1,1′-bis(diphenylphosphino)-ferrocene)dipalladium(II)    -   MTBE=methyl tert-butyl ether    -   RT=room temperature    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran

Reagents and solvents were purchased from commercial suppliers (Aldrich,Fluka, Sigma, etc.), and used without further purification. Reactionswere run under nitrogen atmosphere, unless noted otherwise. Progress ofreaction mixtures was monitored by thin layer chromatography (TLC),analytical high performance liquid chromatography (anal. HPLC), and massspectrometry. Reaction mixtures were worked up as described specificallyin each reaction; commonly they were purified by extraction and otherpurification methods such as temperature-, and solvent-dependentcrystallization, and precipitation. In addition, reaction mixtures wereroutinely purified by preparative HPLC, typically using C18 or BDScolumn packings and conventional eluents. Typical preparative HPLCconditions are described below.

Characterization of reaction products was routinely carried out by massand ¹H-NMR spectrometry. For NMR analysis, samples were dissolved indeuterated solvent (such as CD₃OD, CDCl₃, or d₆-DMSO), and ¹H-NMRspectra were acquired with a Varian Gemini 2000 instrument (400 MHz)under standard observation conditions. Mass spectrometric identificationof compounds was performed by an electrospray ionization method (ESMS)with an Applied Biosystems (Foster City, Calif.) model API 150 EXinstrument or an Agilent (Palo Alto, Calif.) model 1200 LC/MSDinstrument.

General Preparative HPLC Conditions

-   Column: C18, 5 μm. 21.2×150 mm or C18, 5 μm 21×250 or C14 21×150-   Column temperature: Room Temperature-   Flow rate: 20.0 mL/min-   Mobile Phases: A=Water+0.05% TFA    -   B=ACN+0.05% TFA,-   Injection volume: (100-1500 μL)-   Detector wavelength: 214 nm

Crude compounds were dissolved in 1:1 water:acetic acid at about 50mg/mL. A 4 minute analytical scale test run was carried out using a2.1×50 mm C18 column followed by a 15 or 20 minute preparative scale runusing 100 μL injection with the gradient based on the % B retention ofthe analytical scale test run. Exact gradients were sample dependent.Samples with close running impurities were checked with a 21×250 mm C18column and/or a 21×150 mm C14 column for best separation. Fractionscontaining desired product were identified by mass spectrometricanalysis.

Analytical HPLC Methods A, B, C

Column: Zorbax Bonus-RP 3.5 μm. 4.6×150 mm

Column temperature: 35° C.

Flow rate: 1.0 mL/min

Mobile Phases: A=Water/ACN (98:2)+0.1% TFA

-   -   B=Water/ACN (10:90)+0.1% TFA,

Injection volume: 100-1500 μL

Detector wavelength: 254 nm (Methods A and B) 214 nm (Method C)

Sample preparation: Dissolve in 1:1 ACN:water

Gradient Method A

21 min total (time (min)/% B): 0.5/10, 15/60, 16.5/80, 17/80, 18/10,21/10.

Gradient Method B

40 min total (time (min)/% B): 0.5/15, 28/40, 30/80, 33/80, 35/15,40/15.

Gradient Method C

29 min total (time (min)/% B): 0.5/10, 24/90, 25/90, 26/10, 29/10

Preparation 1: 4-(4-bromo-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole

(a) 2-Bromo-1-(4-bromo-phenyl)-ethanone

Bromine (80 g, 500 mmol) was added dropwise to a solution of1-(4-bromo-phenyl)-ethanone (100 g, 500 mmol) in dichloromethane (1500mL) at ambient temperature. The reaction mixture was stirred for 3 h andthen concentrated. The residue was washed with dichloromethane (100 mL)to give the crude title compound (120 g, 86% yield) as a white solid. ¹HNMR (CDCl₃, 400 MHz) δ (ppm): 7.78 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz,2H), 4.32 (s, 2H).

(b) (S)-pyrrolidine-1,2-dicarboxylic acid2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

Diisopropylethylamine (67 g, 518 mmol) was added dropwise to a solutionof the product of the previous step (120 g, 432 mmol) and(S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (L-Boc proline)(102 g, 475 mmol) in acetonitrile (2 L) at room temperature. Thereaction mixture was stirred overnight and concentrated to dryness. Theresidue was dissolved in ethyl acetate (2 L) and washed with water (2L). The organic layer was dried over sodium sulfate and concentrated togive crude title compound (178 g, 100% yield).

(c) (S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of the product of the previous step (178 g, 432 mmol) andammonium acetate (500 g, 6.5 mol) in toluene (2 L) was heated at refluxovernight. The solvent was removed and the residue was dissolved inethyl acetate (2 L) and washed with water (2 L). The organic layer wasdried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography in 1:3 petroleum ether:ethyl acetate togive the title compound (120 g, 71% yield) as a yellow solid. ¹H NMR(CDCl₃, 400 MHz) δ (ppm): 7.56 (s, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.24 (m,1H), 7.14 (s, 1H), 4.88 (m, 1H), 3.33 (m, 2H), 2.94 (s, 1H), 2.07 (m,2H), 1.88 (m, 1H), 1.42 (s, 9H).

(d) 4-(4-bromo-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole

To a solution of(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (3 g, 7.6 mmol) in methanol (3 mL) was added 4NHCl in methanol (60 mL) at 0° C. The reaction mixture was stirred for 2h and then concentrated to give crude hydrochloride salt of the titlecompound (2.51 g 100% yield) as a yellow solid.

Preparation 2: (S)-2-Methoxycarbonylamino-3-methyl-butyric acid

A mixture of (S)-2-amino-3-methyl-butyric acid (10 g, 85 mmol), NaOH(10.3 g, 255 mmol) in water (100 mL) was treated withmethylchloridocarbonate (8 g, 85 mmol) at 0° C. The reaction mixture wasstirred for 24 h at room temperature and then 5 N aqueous HCl was addedto the reaction mixture to adjust pH to 4. The mixture was filteredthrough a pad of Celite to give the product (10 g, 67% yield) as a whitesolid. ¹H NMR (CH₃OD, 400 MHz) δ (ppm) 4.05 (d, 1H), 3.65 (s, 3H), 2.14(m, 1H), 0.95 (m, 6H).

Preparation 3:((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Triethylamine (2.3 g, 11.4 mmol) was added to a solution of4-(4-bromo-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole hydrochloride (2g, 11.4 mol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (2.5 g,7.6 mmol), and HATU (4.3 g, 11.4 mmol) in dimethylformamide (50 mL) at0° C. under nitrogen. The reaction mixture was stirred at roomtemperature overnight and treated with ethyl acetate (100 mL) and water(1000 mL). The organic layer was washed with water (2×100 mL) and brine(100 mL), dried over anhydrous sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography in 1:1petroleum ether:ethyl acetate to give the title compound (2.5 g 74%yield) as a yellow solid. ¹H NMR (d₆-DMSO, 400 MHz) δ (ppm) 7.63 (d,J=8.8 Hz, 2H), 7.54 (m, 1H), 7.47 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 5.03(m, 1H), 4.02 (t, J=8.4 Hz, 1H), 3.76 (m, 2H), 3.51 (s, 3H), 2.10 (m,2H), 1.93 (m, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H).

Preparation 4:((S)-1-{(S)-2-[4-(4′-Amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a mixture of 4-(benzyloxycarbonylamino)phenylboronic acid (1.57 g,5.79 mmol) and((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (1.74 g, 3.86 mmol) in N,N-dimethylformamide (30 mL,400 mmol) was added water (21.91 mL, 1216 mmol) and sodium bicarbonate(2.43 g, 28.96 mmol). The resulting mixture was purged with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (468 mg, 0.41 mmol) was added.The reaction mixture was purged with nitrogen and then heated at 90° C.overnight. The reaction mixture was cooled to RT, diluted with methanol(10 mL), then filtered. The filtrate was concentrated and the crudeproduct was purified by preparative HPLC to give a white solid. (1.28 g)The crude material was dissolved in methanol (40 mL) and then pumpedthrough a continuous flow hydrogenator at 70° C. using a palladiumhydroxide on carbon (20% w/w) cartridge. The resulting solution wasconcentrated to ˜10 mL, treated with Stratospheres™ PL-CO3 resin andstirred at room temperature for 30 min. The reaction mixture wasfiltered and the filtrate was concentrated to give the title compound(680 mg).

Preparation 5:((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2[4-(4-bromo-phenyl)-1H-imidazol-2-A-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (9.10 g, 20.34 mmol) in dioxane:water (3:1) (200 mL),was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.9 g,22.37 mmol), sodium carbonate (4.3 g, 40.68 mmol) and Pd(dppf)₂Cl₂ (0.83g, 5%). The reaction mixture was warmed to reflux under nitrogen,stirred for 4 h, cooled to RT, filtered, and concentrated. The residuewas extracted with ethyl acetate and water, dried with sodium sulfateand concentrated. The crude product was purified by silica gelchromatography eluting with 1:1 hexane:ethyl acetate, to provide thetitle compound (7 g, 75% yield) as a yellow solid. ¹H NMR (CDCl₃, 400MHz) δ (ppm) 7.62-7.55 (m, 1H), 7.50 (d, J=8.0 Hz, 2 H), 7.40 (m, 3H),7.18 (s, 1H), 6.75 (d, J=8.4 Hz, 2H), 5.50 (d, J=9.2 Hz, 1H), 5.25-5.23(m, 1H), 4.31 (t, J=2.4 Hz, 1H), 3.83-3.80 (m, 1H), 3.67 (s, 3H),3.59-3.53 (m, 1H), 3.05-2.95 (m, 1H), 2.40-2.30 (m, 1H), 2.19-2.11 (m,1H), 2.08-2.03 (m, 1H), 1.98-1.93 (m, 1H), 1.07-1.01 (m, 1H), 0.85 (d,J=6.8 Hz, 6 H).

Preparation 6: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid

(a) 4-(4-Ethoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butylester

A mixture of piperazine-1-carboxylic acid tert-butyl ester (18.6 g, 0.1mol), 4-fluoro-benzoic acid ethyl ester (16.8 g, 1 mol) and potassiumcarbonate (0.15 mol) in dimethylsulfoxide (100 mL) was stirred at 120°C. for 24 h. The reaction mixture was cooled to room temperature andpoured into water (1 L). The solid precipitate was filtered, washed withwater, and concentrated to dryness to provide the title compound (20 g,60% yield) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ (ppm) 7.91 (d,2H), 6.83 (d, 2H), 4.30 (q, 2H), 3.55 (m, 4H), 3.26 (m, 4H), 1.46 (s,9H), 1.32 (t, 3H).

(b) 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid

To a mixture of 4-(4-ethoxycarbonyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (10 g, 29.9 mmol) in ethanol (200 mL was added 1 Nsodium hydroxide (100 mL). The reaction mixture was stirred at 70° C.overnight. The solvent was removed under vacuum and the residue washedtwice with ethyl acetate, acidified to pH 6 with 5 N HCl, filtered, andconcentrated to dryness to provide the title compound (8 g, 87% yield)as a white solid. ¹H NMR (d₆-DMSO, 400 MHz) δ (ppm) 7.74 (m, 2H), 6.92(m, 2H), 3.90 (m, 2H), 3.42 (m, 2H), 3.25 (m, 4H), 1.38 (s, 9H).

Preparation 7: 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid

(a) 4-piperazin-1-yl-benzoic acid

A mixture of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (28g, 91 mmol) in hydrochloric acid in methanol (300 mL) was stirred atroom temperature for 4 h. The resulting precipitate was collected byfiltration and concentrated to dryness to provide the title compound (17g, 61% yield) as a white solid.

(b) 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid

To a mixture of 4-piperazin-1-yl-benzoic acid (20 g, 71.6 mmol) andtriethylamine (58 g, 573 mmol) in dichloromethane (500 mL) was addedcyclopropanecarbonyl chloride dropwise at 0° C. The reaction mixture wasstirred at RT overnight. The solvent was removed by rotary evaporation.The residue was diluted with water, treated with sodium hydroxide, andwashed with ethyl acetate and dichloromethane. The aqueous phase wasacidified to pH 6 with 5 N HCl. The resulting precipitate was collectedby filtration and concentrated to dryness to provide the title compound(10 g, 51% yield) as a white solid. ¹H NMR(CH₃OD, 400 MHz) δ (ppm) 7.87(m, 2H), 6.95 (m, 2H), 3.90 (s, 2H), 3.73 (s, 2H), 3.29 (m, 4H), 1.99(m, 1H), 0.86 (m, 4H).

Preparation 8:[(S)-2-Methyl-1-((S)-2-{4-[4′-(4-piperazin-1-yl-benzoylamino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid(365 mg, 1.19 mmol) in dichloromethane (18 mL, 280 mmol) andN,N-dimethylformamide (92.3 uL, 1.19 mmol) was added oxalyl chloride(101 uL, 1.19 mmol). The reaction mixture was stirred for 20 min at roomtemperature and then N,N-diisopropylethylamine (1.42 mL, 8.14 mmol) wasadded followed by((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (500.0 mg, 1.083 mmol) and the mixture was allowed toreact overnight with stirring.

A second solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoicacid (365 mg, 1.19 mmol) and oxalyl chloride (101 uL, 1.19 mmol) indichloromethane (18 mL, 280 mmol) and N,N-dimethylformamide (92.3 uL,1.19 mmol) was prepared and added to the reaction mixture which wasstirred for 1 h. Methanol (10 mL) was added. The mixture wasconcentrated under vacuum and then dissolved in DCM (25 mL) and washedwith saturated aqueous sodium bicarbonate (10 mL). The organic layer wasconcentrated, dissolved in 2.0 M hydrogen chloride in 1,4-dioxane (16.2mL, 16.2 mmol) and ethanol (1.0 mL, 0.17 mmol) and stirred at roomtemperature overnight. The reaction mixture was dissolved in 1:1 aceticacid:water (8.0 mL), and purified by preparative HPLC using a BDS columnto provide the trifluoroacetic acid salt of the title compound. ¹H NMR(d₆-DMSO, 400 MHz) δ (ppm) 10.11 (s, 1H), 8.99-8.77 (m, 2H), 7.92 (dd,J=15.0, 8.9 Hz, 4H), 7.84 (m, 4H), 7.76 (t, J=9.3 Hz, 2H), 7.37-7.25 (m,2H), 7.09 (d, J=9.1 Hz, 2H), 7.02 (d, J=8.9 Hz, 1H), 6.96 (d, J=9.1 Hz,1H), 5.12 (t, J=7.1 Hz, 1H), 4.15-4.06 (m, 1H), 3.90-3.81 (m, 1H),3.66-3.56 (m, 1H), 3.55-3.46 (m, 6H), 3.46-3.39 (m, 2H), 3.39-3.29 (m,2H), 2.43-2.32 (m, 1H), 2.22-1.91 (m, 4H), 0.82 (d, J=6.7 Hz, 3H), 0.77(d, J=6.6 Hz, 3H).

The TFA salt was dissolved in methanol (10 mL) and treated withStratospheres™ PL-CO3 resin and stirred at room temperature for 30 min.The reaction mixture was filtered and the filtrate was concentrated toprovide the title compound (0.354 g).

Preparation 9:[(S)-2-Methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (50 g, 0.11 mol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (57 g,0.22 mol) and potassium acetate (108 g, 1.1 mol) in dioxane (1000 mL)was added Pd(dppf)Cl₂.CH₂Cl₂ (4.5 g, 5.5 mmol) under nitrogen. Thereaction mixture was stirred at 85° C. overnight and then ethyl acetate(100 mL) and water (1000 mL) were added. The organic layer was washedwith water (2×1000 mL) and brine (1000 mL), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography (1:1 petroleum ether:ethyl acetate) to give the titlecompound (22.5 g) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ (ppm)7.71 (m, 3H), 7.32 (m, 1H), 7.19 (m, 1H), 5.56 (m, 1H), 5.18 (m, 1H),4.23 (m, 1H), 3.73 (m, 1H), 3.61 (s, 3H), 3.55 (m, 1H), 2.95 (m, 1H),2.38 (s, 1H), 2.13 (m, 1H), 2.02 (m, 1H), 1.89 (m, 2H), 1.22 (s, 12H),0.79 (d, 6H).

Preparation 10:((S)-1-{(S)-2-[4-(4′-Amino-2′-fluoro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

[(S)-2-Methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (60 mg, 0.12 mmol) and 4-bromo-3-fluoroaniline (23 mg,0.12 mmol) were dissolved in 1,2-dimethoxyethane (1.2 mL, 12 mmol) andwater (0.44 mL, 24 mmol). The reaction mixture was purged with nitrogen.Sodium carbonate (41.6 mg, 0.39 mmol) was added, followed bytetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) and themixture was purged with nitrogen, sealed and heated at 85° C. overnight.The reaction mixture was cooled to room temperature, diluted with ethylacetate (5 mL), and washed with water (5 mL). The organic layer wasconcentrated, dissolved in 1:1 acetic acid:water (8 mL) and purified bypreparative HPLC to produce the TFA salt which was passed throughStratoSpheres™ PL-CO3 resin (0.36 mmol) to provide the title compound(15 mg). (m/z): [M+H]⁺ calcd for C₂₆H₃₀FN₅O₃ 480.23 found 480.4.

Preparation 11:4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-carboxylicacid

To a mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (1.05 g, 2.12 mmol) and 4-iodo-benzoic acid methylester (665 mg, 2.54 mmol) in N,N-dimethylformamide (9.0 mL, 120 mmol) atRT was added water (2.0 mL, 110 mmol) and sodium bicarbonate (711 mg,8.46 mmol). The reaction mixture was flushed with nitrogen, andtetrakis(triphenylphosphine)palladium(0) (122 mg, 0.106 mmol) was addedunder nitrogen. The reaction mixture was flushed with nitrogen and thenheated at 90° C. overnight under an atmosphere of nitrogen.

The reaction mixture was cooled to RT and partitioned between EtOAc(60.0 mL) and water (20.0 mL). The organic layer was washed with water(2×20.0 mL), dried over sodium sulfate, filtered and concentrated togive a black oil, which was purified by silica gel chromatography (24 gsilica gel, 0-100% EtOAc:hexanes). Desired fractions were combined andconcentrated to give a yellowish oil and further dried under vacuum togive a yellowish foam. (956.9 mg).

The product from the previous step was combined with the correspondingproduct of a previous run (total 1.13 g), dissolved in methanol (10.0mL) and water (2.1 mL) and treated with lithium hydroxide monohydrate(564.5 mg) at 60° C. for 3 h. The reaction mixture was concentrated andthe residue was treated with 1:1 acetic acid:water (8.0 mL), andsonicated. Additional TFA (3.0 mL) was and the reaction mixture wassonicated, resulting in a greyish solid precipitate. The reactionmixture was stirred at RT for 10 min and then filtered. The filtrate wasextracted with EtOAc (20.0 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated to give a yellowish oil which wasdissolved in 1:1 acetic acid:water (6.0 mL), and purified by reversephase preparative HPLC. Desired fractions were combined and freeze driedto give a white solid (107.6 mg). The solid from the filtration wastaken up into EtOAc (60.0 mL) and washed with water (2×15.0 mL), aqueoussaturated sodium bicarbonate (20.0 mL), and brine (15.0 mL), dried oversodium sulfate, filtered and concentrated to give the title compound asa yellowish solid (490 mg) (m/z): [M+H]⁺ calcd for C₂₇H₃₀N₄O₅ 491.22found 491.6.

Preparation 12:N-(4-Bromo-phenyl)-4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzamide

A solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid(1.0 g, 3.6 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride (0.70 g, 3.6 mmol) and 1-hydroxy-7-azabenzotriazole (0.50g, 3.6 mmol) in dichloromethane (39 mL, 610 mmol) was stirred for 20 minat room temperature and then p-bromoaniline (0.52 g, 3.0 mmol) andN,N-diisopropylethylamine (2.6 mL, 15 mmol) were added and the reactionmixture was stirred for 2 days. The reaction mixture was filtered; thefiltrate was dissolved in 1:1 acetic acid:water (8 mL). A precipitateformed. This material was filtered to provide the title product as theacetic acid salt (225 mg). (m/z): [M+H]⁺ calcd for C₂₁H₂₂BrN₃O₂ 428.09found 428.0.

Preparation 13:4-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-[4′-((S)-2-pyrrolidin-2-yl-1H-imidazol-4-yl)-biphenyl-4-yl]-benzamide

(a)(S)-2-(4-{4′-[4-(4-Cyclopropanecarbonyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylicacid tert-butyl ester

To a mixture of(S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylicacid tert-butyl ester (1.40 g, 3.19 mmol) andN-(4-bromo-phenyl)-4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzamide(0.910 g, 2.12 mmol) in N,N-dimethylformamide (16.53 mL, 213.5 mmol) atRT was added sodium bicarbonate (1.338 g, 15.93 mmol). Water (12.06 mL,669.2 mmol) was then added. Nitrogen was bubbled through the resultingmixture for 5 min and then tetrakis(triphenylphosphine)palladium(0)(0.258 g, 0.223 mmol) was added. The reaction mixture was heated at 90°C. under nitrogen overnight, cooled to RT, diluted with methanol (30.0mL), and filtered. The filtrate was concentrated and dissolved in ethylacetate (˜3 mL) and hexanes (2 mL) was slowly added to give aprecipitate of crude product. This material was filtered to provide 150mg of the product. The filtrate was concentrated and subjected to thesame precipitation conditions to provide an additional 50 mg of product.This material was combined with the first precipitation crop and wasused without further purification in the next step.

(b)4-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-[4′-((S)-2-pyrrolidin-2-yl1H-imidazol-4-yl)-biphenyl-4-yl]-benzamide

The product of the previous step (200 mg, 0.3 mmol) was dissolved in 4 MHCl in 1,4-dioxane (0.6 mL, 2 mmol). The reaction mixture was stirredfor 4 h, and concentrated under vacuum to provide the title compound asthe HCl salt. (176 mg). (m/z): [M+H]⁺ calcd for C₃₄H₃₆N₆O₂ 561.29 found561.4.

Preparation 14: (R)-Diethylamino-phenyl-acetic acid

Sodium cyanoborohydride (15 g, 238 mmol) was added in portions over afew minutes to a cooled (ice/water) mixture of (R)-amino-phenyl-aceticacid (6.00 g, 39.7 mmol) and methanol (150 mL), and stirred for 5 min.Acetaldehyde (40 mL) was added drop-wise over 10 min. The reactionmixture was stirred at the cooled temperature for 45 min and at ambienttemperature for 6.5 hr. The reaction mixture was again cooled to 0° C.Additional acetaldehyde (60 mL) was then added drop-wise over 10 min.The reaction mixture was stirred at 0° C. for 45 min and at ambienttemperature overnight. The reaction mixture was cooled with an ice-waterbath and treated with water (3 mL). Concentrated HCl was added dropwiseover 45 min until the pH of the mixture was 1.5-2.0. The cooling bathwas removed and stirring was continued while adding concentrated HCl tomaintain the pH of the mixture ˜1.5-2.0. The reaction mixture wasstirred overnight, filtered, and the filtrate was concentrated undervacuum. The crude material was purified by preparative HPLC and washedwith ethyl acetate to afford the title compound as a shiny white solid(5 g, 61% yield). ¹H NMR (d₆-DMSO, 400 MHz) δ (ppm) 7.47 (m, 2H), 7.36(m, 3H), 4.34 (s, 1H), 2.90 (m, 2H), 2.86 (m, 2H), 1.03 (t, 6H).

Preparation 15:{(S)-1-[(S)-2-(5-{4′-[(6-Fluoro-pyridine-3-carbonyl)-amino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[5-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (2000 mg, 4 mmol) dissolved in dichloromethane (27.8mL) and N,N-dimethylacetamide (2.82 mL, 30.3 mmol) was added a solutionof 2-fluoropyridine-5-carbonyl chloride (691 mg, 4.33 mmol) dissolved indichloromethane (6.0 mL) and the reaction mixture mixture was stirred atroom temperature for 30 min. The reaction mixture was concentrated,dissolved in a minimal amount of dichloromethane and ethyl ether wasslowly added until a white precipitate formed. The mixture was sonicatedand filtered to produce the HCl salt of the desired product. The solidwas dissolved in ethyl acetate (20 mL), stirred at room temperature for30 min, and filtered to produce the HCl salt of the title product as afree flowing yellow solid (2.5 g). (m/z): [M+H]⁺ calcd for C₃₂H₃₃FN₆O₄585.26 found 585.5.

Preparation 16:((S)-2-Methyl-1-{(S)-2-[4-(4′-{[6-((S)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

A mixture of the hydrochloride salt of{(S)-1-[(S)-2-(5-{4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (600.0 mg, 0.966 mmol) and(S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.290 g,1.449 mmol) in dimethyl sulfoxide (1.5 mL) and N,N-diisopropylethylamine(1.01 mL, 5.80 mmol) was heated at 120° C. overnight. The reactionmixture was cooled to RT and water (5.0 mL) was added. The resultingmixture was centrifuged and filtered. To the solid was added 4.0 Mhydrogen chloride in 1,4-dioxane (4.9 mL, 20 mmol) and the reactionmixture was stirred at RT for 30 min, and then concentrated. The residuewas coevaporated with ethyl acetate (3×5.0 mL), dissolved in 1:1 aceticacid:water (8 mL), filtered, and purified by reverse phase preparativeHPLC. Desired fractions were combined and freeze dried to give the titlecompound as the trifluoroacetic acid salt (320 mg). (m/z): [M+H]⁺ calcdfor C₃₇H₄₄N₈O₄ 665.36 found 665.4.

Preparation 17:(R)-4-[5-(4-Bromo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

(a) N-(4-Bromo-3-methyl-phenyl)-6-fluoro-nicotinamide

To a solution of 4-bromo-3-methylaniline (200 mg, 1 mmol) dissolved inDCM (4 mL) was slowly added a solution of 2-fluoropyridine-5-carbonylchloride (170 mg, 1.1 mmol) dissolved in DCM (1 mL). A white precipitatewas observed. The reaction mixture was concentrated to produce the HClsalt of the desired product.

(b)(R)-4-[5-(4-Bromo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

The white solid from the previous step was dissolved in dimethylsulfoxide (2 mL, 30 mmol), (R)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester (220 mg, 1.1 mmol) was added, followed byN,N-diisopropylethylamine (2 mL, 10 mmol. The reaction mixture washeated at 120° C. overnight, cooled to RT, and extracted with ethylacetate/water. The organic layer was dried over sodium sulfate,filtered, concentrated, and purified by silica gel chromatography (0-40%ethyl acetate:hexanes) to produce the title compound as a light yellowsolid (200 mg, 40% yield). (m/z): [M+H]⁺ calcd for C₂₃H₂₉BrN₄O₃ 489.15found 489.4.

Preparation 18:((S)-2-Methyl-1-{(S)-2-[4-(2′-methyl-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

(a)(R)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-methyl-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (200 mg, 0.41 mmol) and(R)-4-[5-(4-bromo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (200 mg, 0.4 mmol; Preparation 17) was dissolvedin 1,2-dimethoxyethane (4.25 mL, 40.9 mmol) and water (0.74 mL, 40.9mmol) and the mixture was sparged under nitrogen. Sodium bicarbonate(129 mg, 1.53 mmol) was added, followed bytetrakis(triphenylphosphine)palladium(0) (70.8 mg, 0.0613 mmol). Thereaction mixture was further sparged with nitrogen, sealed undernitrogen and heated at 90° C. overnight. The reaction mixture wasextracted with ethyl acetate (5 mL) and water (3 mL); the organic layerwas dried over sodium sulfate, filtered and concentrated to produce abrown oil, which was purified by reverse phase HPLC to produce thedi-TFA salt of the title intermediate. (m/z): [M+H]⁺ calcd forC₄₃H₅₄N₈O₆ 779.43 found 779.5.

(b)((S)-2-Methyl-1-{(S)-2-[4-(2′-methyl-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

The TFA salt of the previous step was treated with 4 M HCl in1,4-dioxane (3 mL, 10 mmol) and stirred at room temperature for 1 h. Thereaction mixture was concentrated and evaporated with ethyl acetate (2×)to produce the tri-HCl salt of the title compound as a yellow solid (180mg, 60% total yield). (m/z): [M+H]⁺ calcd for C₃₈H₄₆N₈O₄ 679.37 found679.7.

Preparation 19: (S)-1-Acetyl-2-methyl-pyrrolidine-2-carboxylic acid

To a solution of (S)-2-methyl-pyrrolidine-2-carboxylic acid (50.0 mg,0.387 mmol) dissolved in N,N-dimethylacetamide (1.5 mL, 16 mmol) wasadded a solution of acetyl chloride (31.9 mg, 0.406 mmol) dissolved inN,N-dimethylacetamide (0.5 mL), and then N,N-diisopropylethylamine (1mL, 6 mmol) was added and the reaction mixture stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated toproduce the title compound as a light brown oil (30 mg, 40% yield).(m/z): [M+H]⁺ calcd for C₈H₁₃NO₃ 172.10 found 172.2.

Preparation 20:(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid

To a solution of (S)-2-methoxycarbonylamino-3-butyric acid (543 mg, 3.10mmol) dissolved in N,N-dimethylacetamide (10 mL, 11 mmol) was added HATU(1413 mg, 3.72 mmol) followed by N,N-diisopropylethylamine (1.62 mL,9.29 mmol). The reaction mixture stirred for 10 min and then(S)-2-methyl-pyrrolidine-2-carboxylic acid (400 mg, 3.10 mmol) wasadded. The reaction mixture was stirred at room temperature overnight,concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water(5 mL), filtered, and purified by preparative HPLC. Fractions withdesired molecular weight were combined and lyophilized to give the titlecompound (604 mg 68% yield). [M+H]⁺ calcd for C₁₃H₂₂N₂O₅ 287.15 found287.0

Preparation 21(R)-4-[5-(4-Bromo-3-ethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

(a) N-(4-Bromo-3-ethoxy-phenyl)-6-fluoro-nicotinamide

To a solution of 4-bromo-3-ethoxyaniline hydrochloride (500 mg, 2 mmol)dissolved in DCM (7 mL) was slowly added a solution of2-fluoropyridine-5-carbonyl chloride (240 mg, 1.5 mmol) dissolved in DCM(1.2 mL). A white precipitate was observed. The reaction mixture wasstirred for 1 h, and concentrated to produce the HCl salt of the titleintermediate.

(m/z): [M+H]⁺ calcd for C₁₄H₁₂BrFN₂O₂ 339.01 found 339.0.

(b)(R)-4-[5-(4-Bromo-3-ethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

The white solid from the previous step was dissolved in DMSO (3.2 mL, 44mmol), (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (300mg, 1.5 mmol) was added, followed by N,N-diisopropylethylamine (2.6 mL,14.8 mmol). The reaction mixture was heated at 120° C. overnight, cooledto room temperature, and extracted with ethyl acetate/water. The organiclayer was dried over sodium sulfate, filtered, concentrated, andpurified by silica gel chromatography (0-40% ethyl acetate:hexanes) toproduce the title compound as a light yellow solid (324 mg, 42% yield).(m/z): [M+H]⁺ calcd for C₂₄H₃₁BrN₄O₄ 519.15 found 519.5.

Preparation 22:((S)-1-{(S)-2-[4-(2′-Ethoxy-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a)(R)-4-[5-(2-Ethoxy-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (253 mg, 0.52 mmol) and the TFA salt of(R)-4-[5-(4-bromo-3-ethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid ten-butyl ester (324 mg, 0.52 mmol; Preparation 21) was dissolvedin 1,2-dimethoxyethane (5.32 mL, 51.2 mmol) and water (0.92 mL, 51.2mmol) and the mixture was sparged under nitrogen. Sodium bicarbonate(161 mg, 1.92 mmol) was added, followed bytetrakis(triphenylphosphine)palladium(0) (89 mg, 0.077 mmol). Thereaction mixture was further sparged with nitrogen, sealed undernitrogen and heated at 90° C. overnight. The reaction mixture wasextracted with ethyl acetate and water. The organic layer was dried oversodium sulfate, filtered and concentrated to produce the titleintermediate as a brown oil. (m/z): [M+H]⁺ calcd for C₄₄H₅₆N₈O₇ 809.43found 809.6.

(b)((S)-1-{(S)-2-[4-(2′-Ethoxy-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The brown oil of the previous step was treated with 4 M HCl in1,4-dioxane (3.8 mL, 15.3 mmol) and stirred at room temperature for 1 h.The reaction mixture was concentrated and evaporated with ethyl acetate(2×) to produce to produce a brown solid. The solid was dissolved in 1:1acetic acid:water solution (4 mL), filtered, and purified by reversephase HPLC to produce the tri-TFA salt of the title compound as a yellowsolid. (m/z): [M+H]⁺ calcd for C₃₉H₄₈N₈O₅ 709.37 found 709.9.

Preparation 23-1:(R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

(a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (300 mg, 1 mmol)dissolved in DCM (5 mL) was slowly added a solution of2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM(1 mL). A white precipitate was observed. The reaction mixture wasconcentrated to produce the HCl salt of the title intermediate. (m/z):[M+H]⁺ calcd for C₁₃H₇BrF₄N₂O₂ 378.96 found 379.0.

(b)(R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

The white solid from the previous step was dissolved in DMSO (2 mL) and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (230 mg, 1.2mmol) was added, followed by N,N-diisopropylethylamine (2 mL, 10 mmol).The reaction mixture was heated at 120° C. overnight, cooled to roomtemperature, and extracted with ethyl acetate/water. The organic layerwas dried over sodium sulfate, filtered, concentrated, and purified bysilica gel chromatography (0-40% ethyl acetate:hexanes) to produce thetitle compound as a light yellow solid (200 mg, 40% yield). (m/z):[M+H]⁺ calcd for C₂₃H₂₆BrF₃N₄O₄ 559.11, 561.11 found 561.0.

Preparation 23-2:(R)-4-[5-(4-Bromo-3-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

Following the procedure of Preparation 23-1 substituting5-amino-2-bromobenzotrifluoride (300 mg, 1 mmol) for4-bromo-3-trifluoromethoxy-phenylamine (300 mg, 1 mmol), the titleintermediate was prepared (m/z): [M+H]⁺ calcd for C₂₃H₂₆BrF₃N₄O₃ 543.11,545.11 found 545.4.

Preparation 24:((S)-2-Methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (360 mg, 0.64 mmol) and(R)-4-[5-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (360 mg, 0.64 mmol; Preparation 23-1) wasdissolved in 1,2-dimethoxyethane (6.69 mL, 64.4 mmol) and water (1.16mL, 64.4 mmol) and the mixture was sparged under nitrogen. Sodiumbicarbonate (203 mg, 2.41 mmol) was added, followed bytetrakis(triphenylphosphine)palladium(0) (112 mg, 0.097 mmol). Thereaction mixture was further sparged with nitrogen, sealed undernitrogen and heated at 90° C. overnight. The reaction mixture wasextracted with ethyl acetate (5 mL) and water (3 mL); the organic layerwas dried over sodium sulfate, filtered and concentrated to produce abrown oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(4 mL, 20 mmol) and stirred at room temperature for 1 h. The reactionmixture was concentrated and evaporated with ethyl acetate (2×) toproduce the HCl salt of the title compound as a yellow solid which waspurified by preparative HPLC to provide the tri-TFA salt of the titlecompound (150 mg, 21% overall yield). (m/z): [M+H]⁺ calcd forC₃₈H₄₃F₃N₈O₅ 749.33 found 749.5.

Preparation 25:((S)-2-Methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (280 mg, 0.57 mmol) and(R)-4-[5-(4-bromo-3-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (300 mg, 0.72 mmol; Preparation 23-2) wasdissolved in 1,4-dioxane (5.8 mL, 75 mmol) and water (0.83 mL, 46 mmol).Cesium carbonate (560 mg, 1.7 mmol) was added, the reaction mixture wassparged with nitrogen and thenchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)methyl-t-butylether adduct (28 mg, 0.034 mmol) was added. The reactionmixture was sealed with nitrogen and heated at 95° C. for 3 h. Thereaction mixture was extracted with ethyl acetate and water; the organiclayer was dried over sodium sulfate, filtered and concentrated toproduce an orange oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(4 mL, 20 mmol) and stirred at room temperature for 1 h. The reactionmixture was concentrated and evaporated with ethyl acetate (2×) toproduce the HCl salt of the title compound as a yellow solid which waspurified by preparative HPLC to provide the tri-TFA salt of the titlecompound (150 mg, 24% overall yield). (m/z): [M+H]⁺ calcd forC₃₈H₄₃F₃N₈O₄ 733.34 found 733.5.

Preparation 26:(2S,5R)-4-(5-Carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

(a)(2S,5R)-4-(5-Methoxycarbonyl-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of 6-fluoronicotinic acid methyl ester (200 mg, 1.29 mmol) and(2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester washeated at 120° C. in DMSO (2.0 mL) with potassium carbonate (178 mg,1.29 mmol) for 2 h. The reaction mixture was partitioned between ethylacetate (20.0 mL) and water (5.0 mL). The organic layer was washed withwater (2×5.0 mL), dried over sodium sulfate, filtered and concentratedto give the title intermediate as a yellowish oil.

(b)(2S,5R)-4-(5-Carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

The oil of the previous step was dissolved in methanol (10.0 mL, 247mmol) and water (2.5 mL, 140 mmol) and treated with lithium hydroxidemonohydrate (108 mg, 2.58 mmol) at 40° C. overnight. The reactionmixture was concentrated; the residue was dissolved in 1:1 aceticacid:water solution (6 mL), filtered, and purified by reverse phaseHPLC. Desired fractions were combined and freeze dried to give thetri-TFA salt of the title compound as a white solid (327 mg, yield 56%).(m/z): [M+H]⁺ calcd for C₁₇H₂₅N₃O₄ 336.18 found 336.5.

Preparation 27:(2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (190 mg, 0.74mmol) and N,N-diisopropylethylamine (0.65 mL, 3.73 mmol; inN,N-dimethylacetamide (3 mL) was added a solution of(2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester TFA (330 mg, 0.74 mmol; Preparation 26) and HCTU(401 mg, 0.97 mmol) in N,N-dimethylacetamide (3 mL). The reactionmixture was heated at 50° C. overnight. The reaction mixture wasconcentrated by rotary evaporation, extracted with ethyl acetate/sat.sodium carbonate, dried over sodium sulfate, filtered, concentrated andpurified by silica gel chromatography (0-50% ethyl acetate:hexanes) toprovide the title compound (155 mg, yield 36%). (m/z): [M+H]⁺ calcd forC₂₄H₂₈BrF₃N₄O₄ 573.12, 575.12 found 575.5.

Preparation 28:((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (86 mg, 0.17 mmol) and(2S,5R)-4-[5-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (100 mg, 0.2 mmol, Preparation 27) was dissolvedin 1,4-dioxane (1.8 mL, 23 mmol) and water (0.25 mL, 14 mmol). Cesiumcarbonate (170 mg, 0.52 mmol) was added. The reaction mixture wassparged with nitrogen and then tetrakis(triphenylphosphine)palladium(0)(12.1 mg, 0.011 mmol) was added. The reaction mixture was sealed undernitrogen and heated at 95° C. overnight. The reaction mixture wasextracted with ethyl acetate/water, the organic layer was dried oversodium sulfate and concentrated to produce an orange oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(2 mL, 7 mmol) and stirred at room temperature for 1 h. The reactionmixture was concentrated and evaporated with ethyl acetate (2×) toproduce the HCl salt of the title compound as a yellow solid which waspurified by preparative HPLC to provide the tri-TFA salt of the titlecompound (150 mg, 30% overall yield). (m/z): [M+H]⁺ calcd forC₃₉H₄₅F₃N₈O₅ 763.35 found 763.7.

Preparation 29-A:((S)-1-{(S)-2-[4-(4-Bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a) 4-Bromo-N-methoxy-3,N-dimethyl-benzamide

A mixture of 4-bromo-3-methyl-benzoic acid (15 g, 0.069 mol),O,N-dimethyl hydroxylamine (6.5 g, 0.1 mol) HATU (38 g, 0.1 mol), andtriethylamine (20 g, 0.2 mol) dissolved in DMF (50 mL) was stirred at RTfor 12 h, concentrated, and purified by silica gel chromatography (1:1EtOAc:petroleum ether) to provide the title intermediate (11 g, 61%yield) ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.52 (m, 2H), 7.32 (m, 1H), 3.50(s, 3H), 3.29 (m, 3H), 2.38 (s, 3H).

(b) 1-(4-Bromo-3-methyl-phenyl)-ethanone

Methyl lithium (24 mL, 0.038 mol) was added to a solution of the productof the previous step (9 g, 0.035 mol) in THF (20 mL) at −78° C. and thereaction mixture was stirred at RT for 12 h. The organic layer waswashed with aqueous ammonium chloride (20 mL), dried over sodiumsulfate, filtered, concentrated and purified by silica gelchromatography (1:5 EtOAc:petroleum ether) to provide the titleintermediate (6 g, 81% yield) ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.79 (m,1H), 7.59 (m, 2H), 2.55 (d, J=2.8 Hz, 3H), 2.43 (d, J=0.4 Hz, 3H)

(c) 2-Bromo-1-(4-bromo-3-methyl-phenyl)-ethanone

Trimethyl phenylammonium tribromide (13 g, 0.036 mol) was added to asolution of 1-(4-bromo-3-methyl-phenyl)-ethanone (6.3 g, 0.030 mol) inTHF (30 mL) and the reaction mixture was stirred at RT for 12 h,filtered, and concentrated to provide the title intermediate (8.6 g,100% yield). ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.82 (m, 1H), 7.66 (m,2H), 4.38 (s, 2H), 2.56 (s, 3H)

(d) (S)-Pyrrolidine-1,2-dicarboxylic acid2-[2-(4-bromo-3-methyl-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

A mixture of the product of the previous step (8.6 g, 0.03 mol),(S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (9.5 g, 0.044mol), and potassium carbonate (12.4 g, 0.09 mol) was dissolved in ACN(50 mL) and the reaction mixture was stirred at RT for 12 h andconcentrated to provide the title intermediate (13 g, 100% yield) (m/z):[M+H-Boc]⁺ calcd for C₁₉H₂₄BrNO₅ 326.04 found 326.0.

(e)(S)-2-[4-(4-Bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

A mixture of the product of the previous step (13 g, 0.029 mol) andammonium acetate (47 g, 0.61 mol) dissolved in toluene (100 mL) wasstirred at 110° C. for 12 h, concentrated, and purified by silica gelchromatography (1:1 EtOAc:petroleum ether) to provide the titleintermediate (8 g, 68% yield). ¹H NMR (CDCl₃, 400 MHz) δ (ppm): 7.40 (m,3H), 7.13 (m, 1H), 4.89 (m, 1H), 3.34 (m, 2H), 2.94 (m, 1H), 2.34 (s,3H), 2.10 (m, 2H), 1.88 (m, 1H), 1.58 (m, 10H).

(f) 4-(4-Bromo-3-methyl-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole

To a solution of the product of the previous step (8 g, 0.020 mol) inmethanol (3 mL) was added 4 N HCl in methanol (50 mL) at 0° C. Thereaction mixture was stirred at RT for 4 h, and concentrated to give thetitle intermediate (6 g, 100% yield) as a yellow solid. (m/z): [M+H]⁺calcd for C₁₄H₁₆BrN₃ 306.06 found 307.7.

(g)((S)-1-{(S)-2-[4-(4-Bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of the product of the previous step (6 g, 0.018 mol),(S)-2-methoxycarbonylamino-3-methyl-butyric acid (4.6 g, 0.026 mol),HATU (10 g, 0.026 mol), and triethylamine (5.3 g, 0.078 mol) dissolvedin DCM (50 mL) was stirred at RT for 12 h, concentrated and purified bysilica gel chromatography (1:1 EtOAc:petroleum ether) to provide thetitle intermediate (5.5 g, 69% yield). ¹H NMR (CDCl₃, 400 MHz) δ (ppm):10.4 (s, 1H), 7.64 (m, 1H), 7.46 (m, 2H), 7.17 (m, 1H), 5.50 (m, 1H),5.39 (m, 1H), 4.34 (m, 1H), 3.86 (m, 1H), 3.69 (s, 3H), 3.60 (m, 1H),2.45-2.01 (m, 6H), 1.07 (m, 1H), 0.851 (m, 6H).

Preparation 29-B:((S)-1-{(S)-2-[4-(4′-Amino-2,2′-dimethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Potassium carbonate (224 mg, 1.619 mmol) was added to a mixture of((S)-1-{(S)-2-[4-(4-bromo-3-methyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (150 mg, 0.324 mmol) and3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(90.6 mg, 0.389 mmol) in toluene (0.6 mL, 6 mmol) and water (0.3 mL, 20mmol). The reaction mixture was degassed and flushed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (44.9 mg, 0.039 mmol) was addedunder nitrogen and then the reaction mixture was capped and heated at100° C. overnight, cooled to RT and partitioned between ethyl acetate(10 mL) and water (2 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated to give a brownish oil, which waspurified by silica gel chromatography (12 g silica gel, 0-100%EtOAc/hexanes). Desired fractions were combined and concentrated to givethe title compound as a light yellowish foam (135 mg, 85% yield). (m/z):[M+H]⁺ calcd for C₂₈H₃₅N₅O₃ 490.27 found 490.6.

Preparation 30:((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2,2′-dimethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a)(2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2,2′-dimethyl-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of(2S,5R)-4-(5-carboxy-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester TFA (80.8 mg, 0.180 mmol), EDC (34.4 mg, 0.180mmol), and HOAt (24.5 mg, 0.180 mmol) in DMA (2.0 mL, 22 mmol)) wasstirred at RT for 20 min and then((S)-1-{(S)-2-[4-(4′-amino-2,2′-dimethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (80.0 mg, 0.163 mmol; Preparation 29-B) was addedfollowed by N,N-diisopropylethylamine (0.142 mL, 0.817 mmol). Theresulting mixture was heated at 50° C. overnight. The reaction mixturewas partitioned between EtOAc (10 mL) and water (2 mL). The organiclayer was washed with water (2 mL), dried over sodium sulfate, filteredand concentrated to give a yellowish oil. (m/z): [M+H]⁺ calcd forC₄₅H₅₈N₈O₆ 807.45 found 807.6.

(b)((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2,2′-dimethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The oily residue from the previous step was treated with 4 M HCl in1,4-dioxane (1.5 mL, 6.0 mmol) at RT for 30 min. The reaction mixturewas concentrated, the residue was dissolved in 1:1 acetic acid:watersolution (8 mL), filtered, and purified by reverse phase HPLC. Desiredfractions were combined and freeze dried to give the tri-TFA salt of thetitle compound as a white solid (66 mg, yield 39%). (m/z): [M+H]⁺ calcdfor C₄₀H₅₀N₈O₄ 707.40 found 707.8.

Preparation 31:(R)-4-[5-(4-Bromo-3,5-difluoro-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 4-bromo-3,5-difluoroaniline (250 mg, 1.2 mmol)dissolved in DCM (5 mL) was added a solution of2-fluoropyridine-5-carbonyl chloride (190 mg, 1.2 mmol) dissolved in DCM(2 mL) followed by addition of N,N-diisopropylethylamine (100 uL, 0.60mmol). The reaction mixture was stirred at RT for 1 h, and concentratedto produce a clear oil.

The oil from the previous step was dissolved in DMSO (2.6 mL, 36 mmol)and (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (240 mg,1.2 mmol) and N,N-diisopropylethylamine (2.1 mL, 12 mmol) was added. Thereaction mixture was heated at 120° C. overnight and extracted withethyl acetate/water. The organic layer was dried over sodium sulfate,filtered, concentrated and purified by silica gel chromatography (0-40%ethyl acetate:hexanes) to produce the title product as a white solid(yield 62%). (m/z): [M+H]⁺ calcd for C₂₂H₂₅BrF₂N₄O₃ 511.11. 513.11 found513.4.

Preparation 32:((S)-1-{(S)-2-[4-(2′,6′-Difluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Following the procedure of Preparation 24 at the 0.4 mmol scalesubstituting the product of Preparation 31 for the product ofPreparation 23-1, the tri-TFA salt of the title compound was prepared.(m/z): [M+H]⁺ calcd for C₃₇H₄₂F₂N₈O₄ 701.33 found 701.4.

Preparation 33:(R)-4-(5-Carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 6-fluoronicotinic acid (150 g, 1.063 mol) and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (234.2 g,1.169 mol) in tetrahydrofuran (1.75 L) was cooled to −40° C. and then 2M isopropylmagnesium chloride in tetrahydrofuran (1.196 L, 2.39 mol) wasadded slowly maintaining the temperature less than −20° C. The reactionmixture was slowly warmed to RT, stirred at RT for 4 h and then 1 N HCl(1.75 L) and water (1.175 L) were added. The reaction mixture wasextracted with ethyl acetate (4 L). The organic phase was evaporated toprovide crude solid (534 g). To the crude solid was added acetone (2 L)and water (200 mL). The resulting reaction mixture was heated to 50° C.and then water (2.8 L) was added slowly. Seed crystals from a previousrun at smaller scale were added after ˜1 L of water. The reactionmixture was cooled to 20° C. over 3 h, stirred at 20° C. overnight andfiltered. The solid was washed with 2:3 acetone:water (2×500 mL) anddried under vacuum to provide the title compound (329 g, 96% yield) asan off-white solid. HPLC Method A: Retention time 9.73 min.

Preparation 34:(R)-4-[5-(4-Bromo-3-fluoro-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

A solution of(R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester (150 mg, 0.47 mmol, Preparation 33), EDC (130 mg, 0.70mmol), and HOAt (95 mg, 0.70 mmol) dissolved in DMA (4.3 mL, 47 mmol)was stirred at RT for 30 min and then 4-bromo-3-fluoroaniline (89 mg,0.47 mmol) was added, followed by N,N-diisopropylethylamine (0.2 mL, 1.2mmol). The reaction mixture was stirred at RT overnight and extractedwith ethyl acetate/water. The organic layer was dried over sodiumsulfate, filtered, concentrated, and purified by silica gelchromatography (eluted: 0-40% EtOAc:hexanes) to provide the titlecompound as a light yellow oil (100 mg, 40% yield). (m/z): [M+H]⁺ calcdfor C₂₂H₂₆BrFN₄O₃ 493.12 found 493.2.

Preparation 35:((S)-1-{(S)-2-[4-(2′-Fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (99 mg, 0.20 mmol) and(R)-4-[5-(4-bromo-3-fluoro-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (100 mg, 0.2 mmol, Preparation 34) was dissolvedin 1,2-dimethoxyethane (2.06 mL, 19.9 mmol) and Water (0.358 mL, 19.9mmol) and the mixture was sparged under nitrogen. Sodium bicarbonate(62.6 mg, 0.75 mmol) was added, followed bytetrakis(triphenylphosphine)palladium(0) (34.4 mg, 0.030 mmol). Thereaction mixture was further sparged with nitrogen, sealed undernitrogen, and heated at 90° C. overnight. The reaction mixture wasextracted with ethyl acetate (5 mL) and water (3 mL); the organic layerwas dried over sodium sulfate, filtered, and concentrated to produce abrown oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(3 mL, 10 mmol), stirred at room temperature for 1 h, concentrated, andevaporated with ethyl acetate (2×) to produce the HCl salt of the titlecompound as a yellow solid, which was purified by reverse phase HPLC toyield the tri-TFA salt of the title compound (100 mg). (m/z): [M+H]⁺calcd for C₃₇H₄₃FN₈O₄ 683.34 found 683.8.

Preparation 36:6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinicacid

(a) 6-((R)-2-Methyl-piperazin-1-yl)-nicotinic acid methyl ester

To a mixture of(R)-4-(5-carboxy-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester (50 g, 0.156 mol) and methanol (500 mL) was slowlyadded concentrated sulfuric acid (37 mL). The reaction mixture waswarmed to 64° C., stirred at 64° C. overnight, cooled to RT and then icewater (800 mL) was added followed by 50% aqueous sodium hydroxide (60mL). The reaction mixture was extracted with ethyl acetate (3×800 mL).Combined organic layers were dried over sodium sulfate and evaporated togive the title intermediate as an oil. HPLC Method A: Retention time3.50 and 3.72 min.

(b)6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinicacid methyl ester

To a cooled solution of the oil from the previous step indimethylformamide (600 mL) was added(S)-2,2-dimethyl-cyclopropanecarboxylic acid (16.89 g, 0.148 mol) andHCTU (61.23 g 0.148 mol), followed by N,N-diisopropylethylamine (51.6mL, 0.296 mol). The reaction mixture was stirred at RT overnight,diluted with ethyl acetate (1 L) and washed with 1:1 sodiumcarbonate:water. The aqueous phase was extracted with ethyl acetate (500mL). Combined organic phases were washed with saturated aqueous sodiumbicarbonate (500 mL) and water (1 L). The organic layer was extractedwith 3 N HCl (2×500 mL, 300 mL) and then 50% aqueous NaOH (169 g) wasadded to the combined aqueous extract. After 30 min, the reactionmixture was filtered to give a solid (51.1 g). To the crude solid wasadded acetone (300 mL), followed by water (450 mL). The reaction mixturewas stirred at RT overnight and filtered to give the title intermediate(36.86 g, 71.5% y over two steps) as a slightly yellow solid. HPLCMethod B: Retention time 15.05 min.

(c)6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinicacid

To a mixture of the product of the previous step (35.0 g, 0.106 mol) andmethanol (280 mL) was added 2 M LiOH in water (106 mL, 0.211 mol)keeping the temperature under 30° C. The reaction mixture was stirred atRT overnight, concentrated under reduced pressure, and then ethanol (64mL) was added, followed by 1 N HCl (230 mL). Seed crystals from aprevious run at smaller scale were added after 160 mL HCl. After 1 h,the mixture was filtered to give the title compound (33.2 g, 99% yield)as a pale yellow solid. HPLC Method B: Retention time 8.27 min.

Preparation 37:((S)-1-{(S)-2-[4-(4′-Amino-2′-chloro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Saturated aqueous sodium carbonate (0.2 mL) was added to a mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (100 mg, 0.20 mmol), 4-bromo-3-chloroaniline (46 mg,0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),and water (0.3 mL). The reaction mixture was purged with nitrogen andthen 1,4-dioxane (0.7 mL) was added. The reaction mixture was degassed,stirred, and heated at 90° C. overnight. Water and ethyl acetate wereadded; the reaction mixture was concentrated; dissolved in 1:1 aceticacid:water (1 mL) and purified by preparative HPLC. Fractions werecombined, adjusted to pH 8-9 with aqueous sodium bicarbonate, andextracted with DCM. Extracts were washed with water, dried with sodiumsulfate, and concentrated. The concentrate was dissolved in methanol andconcentrated under vacuum to provide the title compound (m/z): [M+H]⁺calcd for C₂₆H₃₀ClN₅O₃ 496.20 found 496.7.

Preparation 38-A:((S)-1-{(S)-2-[4-(4-Bromo-3-fluoro-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a) 1-(4-Bromo-3-fluoro-phenyl)-2-chloro-ethanone

Oxalyl dichloride (6.1 g, 48 mmol) was added to a solution of4-bromo-3-fluoro-benzoic acid (7 g, 32 mmol) in DCM (80 mL) at 0° C.followed by DMF (0.2 mL) and the reaction mixture was stirred at RT for2 h and then conentrated under vacuum to provide crude4-bromo-3-fluoro-benzoyl chloride.

To the crude product dissolved in DCM (50 mL) was added 2 Ntrimethylsilyldiazomethane (48 mL, 96 mmol) at 0° C. and the reactionmixture was stirred at RT for 3 h. Acetic acid was added and thereaction mixture was diluted with DCM, washed with brine, andconcentrated to provide crude1-(4-bromo-3-fluoro-phenyl)-2-diazenyl-2-trimethylsilanyl-ethanone (8.0g).

To a solution of the product of the previous step (8.0 g) in THF (50 mL)was added 4 N HCl in dioxane (20 mL) at 0° C. and the reaction mixturewas stirred at RT for 3 h, concentrated, and EtOAc (100 mL) was added.The solution was washed with sodium bicarbonate, dried, concentrated,and purified by silica gel chromatography (eluted with 5:1 petroleumether:EtOAc) to give the title intermediate (6.5 g, 81% yield). (m/z):[M+H]⁺ calcd for C₈H₅BrClFO 252.93 found 252.7. ¹H NMR (CDCl₃, 400 MHz)δ (ppm): 7.72-7.76 (2H, M), 7.63-7.65 (1H, m), 4.64 (2H, s).

(b) (S)-Pyrrolidine-1,2-dicarboxylic acid2-[2-(4-bromo-3-fluoro-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

To a solution of the product of the previous step (6.1 g, 28.4 mmol) inDMF (100 mL) was added (S)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (6.5 g, 25.8 mmol) and cesium carbonate (16.8 g, 51.6mmol) and the reaction mixture was stirred at RT for 2 h. Ethyl acetate(500 mL) was added and the solution was washed with brine (4×50 mL),dried, and concentrated to give the title intermediate as a dark oil (10g). (m/z): [M+H-Boc]⁺ calcd for C₁₈H₂₁BrFNO₅ 330.02 found 331.9.

(c)(S)-2-[4-(4-Bromo-3-fluoro-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester

Ammonium acetate (39.8 g, 516 mmol) was added to a solution of theproduct of the previous step (10 g, 25.8 mmol) in toluene (150 mL) andthe reaction mixture was stirred at reflux overnight. Ethyl acetate (200mL) was added, and the solution was washed with water (3×50 mL), dried,concentrated, and purified by silica gel chromatography (eluted with 4:1petroleum ether:EtOAc) to give the title product as a yellow solid (4.2g). (m/z): [M+H]⁺ calcd for C₁₈H₂₁BrFN₃O₂ 410.09 found 409.9. ¹H NMR(CDCl₃, 400 MHz) δ (ppm): 7.41-7.56 (3H, m), 7.25 (1H, s), 4.97 (1H, d),3.43 (2H, m), 3.01 (1H, s), 2.10 (2H, m), 1.98 (2H. m). 1.42-1.51 (10H,m).

(d)((S)-1-{(S)-2-[4-(4-Bromo-3-fluoro-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of the product of the previous step (4.2 g, 10.24 mmol) inmethanol was added 4 N HCl in dioxane (30 mL) and the reaction mixturewas stirred at RT for 2 h and concentrated to give crude4-(4-bromo-3-fluoro-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole (4.1 g)

To a solution of the crude product (4.1 g, 10.24 mmol) in DMF (70 mL)was added (S)-2-methoxycarbonylamino-3-methyl-butyric acid (1.97 g,11.26 mmol), HATU (4.67 g, 12.29 mmol) and triethylamine (3.11 g, 30.72mmol) and the reaction mixture was stirred at RT overnight. Ethylacetate (200 mL) was added, and the solution was washed with brine (3×40mL), dried, filtered, concentrated, and purified by silica gelchromatography (eluted with 2:1 petroleum ether:EtOAc) to give the titleproduct as a yellow solid (2.6 g, 54% yield) (m/z): [M+H]⁺ calcd forC₂₀H₂₄BrN₄O₃ 467.11 found 468.9. ¹H NMR (CD₃OD, 400 MHz) δ (ppm):7.51-7.62 (m, 2 H), 7.40-7.42 (m, 2 H), 5.12-5.16 (m, 1 H), 4.22-4.20(m, 1 H), 4.05-3.95 (m, 1 H), 3.88-3.82 (m, 1 H), 3.65 (s, 3 H),2.41-2.11 (m, 3 H), 2.05-1.99 (m, 1 H), 0.97-0.88 (m, 7 H).

Preparation 38-B:((S)-1-{(S)-2-[4-(4′-Amino-2,2′-difluoro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Potassium carbonate (300 mg, 2.1 mmol) was added to a solution of((S)-1-{(S)-2-[4-(4-bromo-3-fluoro-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (200 mg, 0.4 mmol) and3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(130 mg, 0.55 mmol) dissolved in toluene (0.91 mL, 8.6 mmol) and water(0.38 mL, 21 mmol). The reaction mixture was sparged under nitrogen.Tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.051 mmol) was addedand the reaction mixture was sparged with nitrogen and heated at 100° C.overnight. The reaction mixture was diluted in ethyl acetate and washedwith water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated to produce a red solid. (m/z): [M+H]⁺ calcdfor C₂₆H₂₉F₂N₅O₃ 498.20 found 498.5

The red solid was purified by silica gel chromatography (0-100% ethylacetate:hexanes) to produce the desired product as a yellow solid,containing triphenylphosphine oxide. A portion of the yellow solid (50mg) was dissolved in 1:1 acetic acid:water (5 mL) and purified byreverse phase HPLC to produce the TFA salt of the title intermediate asa white powder (210 mg, 99.3% purity).

Preparation 39:((S)-1-{(S)-2-[4-(4′-Amino-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A mixture of 4-bromo-2-fluoro-5-(trifluoromethyl)aniline (78 mg, 0.302mmol) and[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (150 mg, 0.302 mmol) in toluene (0.6 mL, 6 mmol) andwater (0.4 mL, 20 mmol) was purged with nitrogen. Potassium carbonate(208.8 g, 1.511 mmol) and tetrakis(triphenylphosphine)-palladium(0) (35mg, 0.030 mmol) were added under an atmosphere of nitrogen. The reactionmixture was capped and heated at 100° C. overnight, cooled to RT, andpartitioned between ethyl acetate (5.0 mL) and water (1.5 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedto give a yellowish oil, which was purified by silica gel chromatography(12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combinedand concentrated to give the title intermediate as a yellowish solid(128 mg, 77% yield). (m/z): [M+H]⁺ calcd for C₂₇H₂₄F₄N₅O₃ 548.22 found548.6.

Preparation 40:{(S)-1-[(S)-2-(4-{5′-Fluoro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethyl-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4′-amino-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (128 mg, 0.234 mmol; Preparation 39) in DCM (3 mL, 47mmol) and DMA (0.3 mL, 3 mmol) was added 2-fluoropyridine-5-carbonylchloride (37 mg, 0.234 mmol), and the resulting solution was stirred atRT overnight. The reaction mixture was concentrated by rotaryevaporation to give the monoHCl salt of the title intermediate as abrownish oil (163 mg), which was used without further purification.(m/z): [M+H]⁺ calcd for C₃₃H₃₁F₅N₆O₄ 671.23 found 671.7.

Preparation 41:((S)-1-{(S)-2-[4-(5′-Fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A solution of{(S)-1-[(S)-2-(4-{5′-fluoro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethyl-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester HCl (100 mg, 0.141 mmol, Preparation 40),(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (283 mg,1.414 mmol), and N,N-diisopropylethylamine (246.3 uL, 1.414 mmol) wasstirred in DMSO (1.5 mL, 21 mmol) at 120° C. overnight. The reactionmixture was concentrated by rotary evaporation to provide a crudeintermediate which was treated with 4.0 M HCl in 1,4-dioxane (1.0 mL,4.0 mmol) for 1 h, concentrated by rotary evaporation, dissolved in 1:1acetic acid:water (8 mL), filtered and purified by reverse phase HPLC.Fractions were combined and lyophilized to give the tri-TFA salt of thetitle intermediate (54 mg, 35% yield). (m/z): [M+H]⁺ calcd forC₃₈H₄₂F₄N₈O₄ 751.33 found 751.7.

Preparation 42: 4-Bromo-2-fluoro-5-trifluoromethoxy-phenylamine

To a mixture of 2-fluoro-5-(trifluoromethoxy)aniline (1 g, 5 mmol)dissolved in DMF (2 mL) was slowly added a solution ofN-bromosuccinimide (1.1 g, 6.2 mmol) dissolved in DMF (2 mL). Thereaction mixture was stirred at room temperature for 1 h, concentratedand extracted with ethyl acetate/water. The organic layer was dried oversodium sulfate, filtered, concentrated and purified by silica gelchromatography (eluted 0-10% ethyl acetate:hexanes) to produce the titleintermediate as a red oil (818 mg, 58% yield). (m/z): [M+H]⁺ calcd forC₇H₄BrF₄NO 273.94, 275.94 found 276.1.

Preparation 43:((S)-1-{(S)-2-[4-(4′-Amino-5′-fluoro-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Potassium carbonate (350 mg, 2.5 mmol) was added to a solution of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (250 mg, 0.50 mmol) and4-bromo-2-fluoro-5-trifluoromethoxy-phenylamine (140 mg, 0.50 mmol;Preparation 42) dissolved in toluene (2 mL) and water (0.54 mL). Thereaction mixture was sparged under nitrogen.Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was addedand the reaction mixture was sparged with nitrogen and heated at 100° C.overnight. The reaction mixture was diluted in ethyl acetate and washedwith water and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated to produce a red solid, which was purified bysilica gel chromatography (0-100% ethyl acetate:hexanes) to produce thedesired product as a white solid with some triphenylphosphine oxideimpurity. (m/z): [M+H]⁺ calcd for C₂₇H₂₉F₄N₅O₄ 564.2 found 564.4.

The solid (50 mg) was dissolved in 1:1 acetic acid:water (5 mL) andpurified by reverse phase HPLC to produce the TFA salt of the titleintermediate as a white solid

Preparation 44:((S)-1-{(S)-2-[4-(5′-Fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a){(S)-1-[(S)-2-(4-{5′-Fluoro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4′-amino-5′-fluoro-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (50 mg, 0.09 mmol, Preparation 43) in DCM (0.6 mL, 9mmol) was slowly added 2-fluoropyridine-5-carbonyl chloride (10 mg, 0.09mmol;) and the reaction mixture was stirred at room temperature for 5min and then concentrated to provide a colored solid.

(b)(R)-4-[5-(5-Fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert butyl ester

The solid from the previous step was dissolved in a mixture of dimethylsulfoxide (0.20 mL, 2.8 mmol) and N,N-diisopropylethylamine (0.32 mL,1.8 mmol) and then (R)-3-methyl-piperazine-1-carboxylic acid tert-butylester (180 mg, 0.91 mmol) was added and the reaction mixture was heatedat 120° C. overnight and concentrated by rotary evaporation to produce adark colored oil.

(c)((S)-1-{(S)-2-[4-(5′-Fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(2 mL, 8 mmol) and heated at 50° C. for 1 h. The reaction mixture wasconcentrated, and evaporated with ethyl acetate (2×) to produce the HClsalt of the desired product as a solid, which was purified by reversephase HPLC to produce the tri-TFA salt of the desired product as a whitesolid (53 mg, 50% yield). (m/z): [M+H]⁺ calcd for C₃₈H₄₂F₄N₈O₅ 767.32found 767.7

Preparation 45: 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester

(a) 4-Amino-3-trifluoromethoxy-benzoic acid methyl ester

A mixture of 4-amino-3-(trifluoromethoxy)benzoic acid (5 g, 22.61 mmol),methanol (75 mL) and 4.0 M HCl in 1,4-dioxane (56.53 mL, 226.1 mmol) wasstirred at RT for 2 days. The reaction mixture was concentrated and theresulting residue was evaporated with EtOAc (3×20 mL) and dried undervacuum to provide the HCl salt of the title intermediate (6.9 g).

(b) 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester

The product of the previous step (2.00 g, 7.36 mmol) was dissolved in amixture of acetonitrile (89 mL) and water (9.2 mL) at RT. Copper(II)bromide (2.27 g, 10.2 mmol) was added followed by tert-butyl nitrite(1.51 mL, 12.7 mmol) dropwise. The resulting mixture was heated at 70°C. for 1 hour, cooled to RT, and treated wtih saturated sodiumbicarbonate (30 mL). The mixture was extracted with EtOAc (100 mL). Theaqueous layer was extracted with EtOAc (100 mL). Combined organic layerswere washed with brine (30 mL), dried over sodium sulfate, filtered, andconcentrated to give a brownish oil, which was purified by silica gelchromatography, (0-30% EtOAc/hexanes). Desired fractions were combinedand concentrated to give the title intermediate as a light yellowish oil(1.57 g, 71% yield) which was confirmed by NMR.

Preparation 46:4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylicacid

To a mixture of 4-Bromo-3-trifluoromethoxy-benzoic acid methyl ester(331 mg, 1.11 mmol; Preparation 45) and[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (500 mg, 1.01 mmol) in toluene (1 mL) and water (1 mL)at RT was added potassium carbonate (696 mg, 5.04 mmol). The mixture wasdegassed and flushed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.101 mmol) was addedunder niotrogen and then the reaction mixture was capped and was heatedat 100° C. overnight, cooled to RT and partitioned between EtOAc (20 mL)and water (5 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to give a brownish oil.

The oily residue from the previous step was treated with methanol (6 mL)and water (1 mL) and lithium hydroxide monohydrate (254 mg, 6.04 mmol)at 65° C. for 1 hour. The reaction mixture was concentrated and theresulting residue was treated with 1:1 acetic acid:water (20 mL),filtered, and purified by reverse phase HPLC. Desired fractions werecombined and freeze dried to give the TFA salt of the title intermediateas a white solid (190 mg). (m/z): [M+H]⁺ calcd for C₂₈H₂₉F₃N₄O₆ 575.20found 575.5.

Preparation 47: (R)-2-Methyl-1-(5-nitro-pyridin-2-yl)-piperazine

(a) (R)-3-Methyl-4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acidtert-butyl ester

A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol),(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 6.9mmol) and potassium carbonate (1.308 g, 9.46 mmol) in DMSO (20 mL) washeated at 100° C. overnight. The reaction mixture was cooled to RT, andfiltered through a pad of silica gel, eluted with EtOAc (150 mL). Thefiltrate was washed with water (2×20 mL) and brine (20 mL), dried oversodium sulfate, filtered and concentrated to give a brownish oil whichwas purified by silica gel chromatography (80 g silica gel, 0-60%EtOAc/hexanes). Desired fractions were combined and concentrated to givethe title intermediate as a yellowish solid. (m/z): [M+H]⁺ calcd forC₁₅H₂₂N₄O₄ 323.16 found 323.3.

(b) (R)-2-Methyl-1-(5-nitro-pyridin-2-yl)-piperazine

The solid from previous step was treated with 4 M HCl in 1,4-dioxane(47.3 mL) and HCl (11.6 mL) and the reaction mixture was stirred at RTfor 2 h and concentrated to produce a yellow solid, which was evaporatedtwice with ethyl acetate to yield the diHCl salt of the titleintermediate (940 mg, 50% yield) as a yellow solid. (m/z): [M+H]⁺ calcdfor C₁₀H₁₄N₄O₂ 223.11 found 223.2.

Preparation 48:((S)-1-{(S)-2-[(R)-4-(5-Amino-pyridin-2-yl)-3-methyl-piperazine-1-carbonyl]-2-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methylester

(a)((S)-2-Methyl-1-{(S)-2-methyl-2-[(R)-3-methyl-4-(5-nitro-pyridin-2-yl)-piperazine-1-carbonyl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid (770 mg, 2.7 mmol) was dissolved in DMA (17 mL) and HATU (1.0 g,2.7 mmol) was added. The reaction mixture was stirred for 20 min andthen (R)-2-methyl-1-(5-nitro-pyridin-2-yl)-piperazine di-HCl (700 mg, 2mmol; Preparation 47) was added followed by N,N-diisopropylethylamine(2.0 mL, 11 mmol) and the reaction mixture was stirred at 55° C.overnight, cooled to RT, concentrated by rotary evaporation andextracted with EtOAc/water. The organic layer was washed with water, andthen brine, dried over sodium sulfate, concentrated under vacuum, andpurified by silica gel chromatography (0-100% ethyl acetate:hexanes) toyield the title intermediate (970 mg) as a yellow oil. (m/z): [M+H]⁺calcd for C₂₃H₃₄N₆O₆ 491.25 found 491.7.

(b)f(S)-1-{(S)-2-[(R)-4-(5-Amino-pyridin-2-yl)-3-methyl-piperazine-1-carbonyl]-2-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methylester

The oil from the previous step was dissolved in methanol (15 mL) andtreated with 50% wet palladium hydroxide on carbon (20% w/w) (13 mg,0.45 mmol) and stirred for 2 h at RT. The reaction mixture was filteredthrough Celite, and concentrated under vacuum to produce a dark red oil,which was purified by silica gel chromatography (0-100% ethylacetate:hexanes for 15 min then 0-5% methanol:EtOAc for another 15 min)to yield the title intermediate (375 mg; 40% yield) as a reddish solid.(m/z): [M+H]⁺ calcd for C₂₃H₃₆N₆O₄ 461.28 found 461.6.

Preparation 49:(2S,5R)-4-[5-(4-Bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 4-bromo-2-fluoro-5-trifluoromethoxy-phenylamine (500mg, 2 mmol) dissolved in DCM (1 mL) was slowly added a solution of2-fluoropyridine-5-carbonyl chloride (290 mg, 1.8 mmol) in DCM (1 mL). Afew drops of DMA were added and the reaction mixture was concentrated toformN-(4-bromo-2-fluoro-5-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide asa purple solid.

The solid from the previous step was dissolved in a mixture ofN,N-diisopropylethylamine (0.7 mL, 4 mmol) and DMSO (0.7 mL, 10 mmol)and (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester(590 mg, 2.7 mmol) was added and the reaction mixture heated at 120° C.overnight, concentrated by rotary evaporation, dissolved in a smallamount of DCM and purified by silica gel chromatography (0-40% ethylacetate:hexanes) to produce the title intermediate (613 mg, 57% yield)as a white solid. (m/z): [M+H]⁺ calcd for C₂₄H₂₇F₄N₄O₄ 591.12 found591.4.

Preparation 50:((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-5′-fluoro-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (340 mg, 0.68 mmol) and(2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (400 mg, 0.68 mmol; Preparation 49) dissolved intoluene (2.5 mL) and water (0.73 mL). The reaction mixture was spargedunder nitrogen. Tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081mmol) was added and the reaction mixture was sparged with nitrogen andheated at 100° C. for 4 h. The reaction mixture was diluted in ethylacetate and washed with water and brine. The organic layer was driedover sodium sulfate, filtered, and concentrated to produce(2S,5R)-4-[5-(5-fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester as a red solid.

The solid from the previous step was treated with 4 M HCl in 1,4-dioxane(5 mL, 20 mmol) and stirred at 50° C. for 30 min. The reaction mixturewas concentrated, dissolved in 1:1 acetic acid:water (8 mL) and purifiedby reverse phase HPLC. Fractions containing desired compound werecombined and lyophilized to produce the tri-TFA salt of the titleintermediate (490 mg, 64% yield) as a white powder. (m/z): [M+H]⁺ calcdfor C₃₉H₄₄F₄N₈O₅ 781.34 found 781.6.

Preparation 51: 5-Amino-2-bromo-4-chlorobenzotrifluoride

A solution of N-bromosuccinimide (1.0 g, 5.6 mmol) dissolved in DMF (3mL) was slowly added to a mixture of 3-amino-4-chlorobenzotrifluoride (1g, 5 mmol) dissolved in DMF (2 mL) and the reaction mixture was stirredat RT for 20 min, concentrated, and extracted with ethyl acetate/water.The organic layer was dried over sodium sulfate, filtered, concentrated,and purified by flash chromatography (eluted with 100% hexanes) toproduce the title intermediate as a reddish colored oil (970 mg, 70%yield). (m/z): [M+H]⁺ calcd for C₇H₄BrClF₃N, 273.92, 275.92 found 276.2.

Preparation 52((S)-1-{(S)-2-[4-(4′-Amino-5′-chloro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Potassium carbonate (280 mg, 2.0 mmol) was added to a solution of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (200 mg, 0.40 mmol) and5-amino-2-bromo-4-chlorobenzotrifluoride (110 mg, 0.40 mmol; Preparation51) dissolved in toluene (1.3 mL) and water (0.43 mL). The reactionmixture was sparged under nitrogen.Tetrakis(triphenylphosphine)palladium(0) (56 mg, 0.48 mmol) was addedand the reaction mixture was sparged with nitrogen and heated at 100° C.for 4 h. The reaction mixture was diluted in ethyl acetate and washedwith water and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated to produce a red solid, which was purified bysilica gel chromatography (0-100% ethyl acetate:hexanes) to produce thedesired product as a yellow solid.

The solid (˜30 mg) was dissolved in 1:1 acetic acid:water (5 mL) andpurified by reverse phase HPLC to produce the di-TFA salt of the titleintermediate (31.1 mg). (m/z): [M+H]⁺ calcd for C₂₇H₂₉ClF₃N₅O₃ 564.19found 564.2.

Preparation 53:((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacidmethyl ester

To a solution of((S)-1-{(S)-2-[4-(4′-amino-5′-chloro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (50 mg, 0.09 mmol; Preparation 52) dissolved in DCM(0.3 mL) was slowly added a solution of 2-fluoropyridine-5-carbonylchloride (14 mg, 0.091 mmol) dissolved in DCM (0.3 mL). The reactionmixture was stirred at RT for 5 min and concentrated to produce{(S)-1-[(S)-2-(4-{5′-chloro-4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-2′-trifluoromethyl-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester as a yellow solid.

The yellow solid from the previous step was dissolved in a mixture ofDMSO (0.3 mL, 4 mmol) and N,N-diisopropylethylamine (0.3 mL, 2 mmol) and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.91mmol) was added. The reaction mixture was heated at 100° C. for 72 h,and concentrated by rotary evaporation to produce(R)-4-[5-(5-chloro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester as a dark colored oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(2 mL, 8 mmol) and the reaction mixture was stirred at 50° C. for 1 h,and concentrated under vacuum to produce the HCl salt of the desiredproduct, which was dissolved in 1:1 acetic acid:water (5 mL) andpurified by reverse phase HPLC. Fractions containing desired productwere combined and lyophilized to produce the tri-TFA salt of the titleintermediate (30 mg, 30% yield) as a white powder. (m/z): [M+H]⁺ calcdfor C₃₈H₄₂ClF₃N₈O₄ 767.30 found 767.5.

Preparation 54:(2S,5R)-4-[5-(4-Bromo-2-chloro-5-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl

To a solution of 5-amino-2-bromo-4-chlorobenzotrifluoride (466 mg, 1.70mmol) dissolved in DCM (1 mL) was slowly added a solution of2-fluoropyridine-5-carbonyl chloride (270 mg, 1.70 mmol) in DCM (1 mL).A few drops of DMA were added and the reaction mixture was concentratedto formN-(4-bromo-2-chloro-5-trifluoromethyl-phenyl)-6-fluoro-nicotinamide as apurple solid.

Half of the solid from the previous step was treated withN,N-diisopropylethylamine (0.5 mL, 3 mmol), DMSO (0.5 mL, 7 mmol) and(2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (273mg, 1.27 mmol) and the reaction mixture was heated at 120° C. overnight,concentrated by rotary evaporation, dissolved in a small amount of DCMand purified by silica gel chromatography (0-50% ethyl acetate:hexanes)to produce the title intermediate (288 mg, 29% yield) as a yellow solid.(m/z): [M+H]⁺ calcd for C₂₄H₂₇F₄N₄O₄ 591.09, 593.09 found 593.2.

Preparation 55:((S)-1-{(S)-2-[4-5′-Chloro-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Following the procedure of Preparation 50 at the 0.24 mmol scale,substituting(2S,5R)-4-[5-(4-bromo-2-chloro-5-trifluoromethyl-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (140 mg, 0.24 mmol, Preparation 54) for(2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester (Preparation 49), the tri-TFA salt of the titleintermediate (490 mg, 64% yield) was prepared as a white powder. (m/z):[M+H]⁺ calcd for C₃₉H₄₄ClF₃N₈O₄ 781.31 found 781.6.

Preparation 56:{(S)-2-Methyl-1-[(S)-2-(4-{4′46-((R)-2-methyl-piperazin-1-yl)-pyridin-3-ylcarbamoyl]-2′-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

A mixture of4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylicacid TFA (600 mg, 0.9 mmol) and HATU (364 mg, 0.96 mmol) in DMA (8 mL)was stirred at RT for 15 min and then 0.5 M(R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carboxylic acidtert-butyl ester in DMA (1.7 mL) was added followed byN,N-diisopropylethylamine (0.76 mL, 4.36 mmol). The resulting mixturewas heated at 55° C. overnight, washed with EtOAc (100 mL) and water (25mL). The organic layer was washed again with water and then with brine,dried over sodium sulfate, filtered, and concentrated to yield a darkreddish oil which was purified by silica gel chromatography (40 g silicacolumn, 0-80% hexane:EtOAc) to provide(R)-4-{5-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carbonyl)-amino]-pyridin-2-yl}-3-methyl-piperazine-1-carboxylicacid tert-butyl ester (646 mg) as a light brownish solid.

The solid product was treated with 4.0 M HCl in 1,4-dioxane (6.5 mL,26.14 mmol) and HCl (1.6 mL) and the reaction mixture was stirred at RTfor 1 h, concentrated, and evaporated with EtOAc (2×1 mL) to to providethe tri-HCl salt of the title intermediate (693 mg) as a beige solid.(m/z): [M+H]⁺ calcd for C₃₈H₄₃F₃N₈O₅ 749.33 found 749.8.

Preparation 57:((S)-2-Methyl-1-{(S)-2-[4-(4′-{6-[(R)-2-methyl-4-((S)-2-methyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

To a mixture of (S)-2-methyl-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (222 mg, 0.97 mmol) dissolved in DMA (6 mL) was addedHATU (369 mg, 0.97 mmol) and the reaction mixture was stirred for 20 minand then{(S)-2-methyl-1-[(S)-2-(4-{4′-[6-((R)-2-methyl-piperazin-1-yl)-pyridin-3-ylcarbamoyl]-2′-trifluoromethoxy-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester 3 HCl (693 mg, 0.81 mmol; Preparation 56) was addedfollowed by N,N-diisopropylethylamine (0.71 mL, 4.04 mmol). The reactionmixture was stirred at 55° C. overnight, concentrated by rotaryevaporation, and extracted with EtOAc (80 mL) and water (20 mL). Theorganic layer was washed again with water and then with brine, driedover sodium sulfate, filtered, and concentrated under vacuum, andpurified by silica gel chromatography (40 g silica column, 0-100% ethylacetate:hexanes) to yield 537 mg of a light brown solid.

The light brown solid from the previous step was treated with 4 M HCl in1,4-dioxane (6.1 mL, 24.23 mmol) and HCl (1.5 mL) and stirred at RT for1 h, concentrated, and evaporated with ethyl acetate (2×1 mL) to producethe tri-HCl salt of the title intermediate (569 mg) as a light yellowsolid. (m/z): [M+H]⁺ calcd for C₄₄H₅₂F₃N₉O₆ 860.40 found 860.6.

Preparation 58:(2S,5R)-4-[5-(6-Bromo-2-methyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

(a)(2S,5R)-4-(5-Methoxycarbonyl-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of 6-fluoronicotinic acid methyl ester (1.0 g, 6.4 mmol),(2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester HCl(1.6 g, 6.4 mmol), and potassium carbonate (1.78 g, 12.9 mmol) werestirred in DMSO (10 mL) at 120° C. for 2 h, cooled, diluted with ethylacetate (50 mL), washed with water (2×10 mL), dried over magnesiumsulfate, filtered and concentrated.

(b)(2S,5R)-4-(5-Carboxy-pyridin-2-O-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

Lithium hydroxide (618 mg, 12.9 mmol) was added to a solution of theproduct of the previous step in methanol (15 mL) and water (3 mL), andthe resulting mixture was stirred at 40° C. for 5 h, concentrated, andacidified with 1N HCl to pH 4. The resulting mixture was extracted withethyl acetate (2×50 mL). The organic layer was dried over magnesiumsulfate, filtered, concentrated, dissolved in 1:1 acetic acid:water (8mL), filtered and purified by reverse phase HPLC to give the TFA salt ofthe title intermediate (1.55 g, 54% yield). (m/z): [M+H]⁺ calcd forC₁₇H₂₅N₃O₄ 336.18 found 336.4.

(c)(2S,5R)-4-[5-(6-Bromo-2-methyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

The product of the previous step (180.2 mg, 0.40), EDC (115.3 mg, 0.60mmol), and HOAt (81.9 mg, 0.60 mmol) were stirred in DMF (2 mL) atRT for10 min and then 6-bromo-2-methyl-pyridin-3-ylamine (75 mg, 0.40 mmol)and N,N-diisopropylethylamine (0.35 mL, 2.01 mmol) were added, and thereaction mixture was stirred at 50° C. overnight, concentrated by rotaryevaporation, dissolved in 1:1 acetic acid:water (5 mL), filtered, andpurirfied by reverse phase HPLC. Fractions containing desired productwere combined and lyophilized to give the TFA salt of the titleintermediate (91 mg, 37% yield). (m/z): [M+H]⁺ calcd for C₂₃H₃₀BrN₅O₃504.15 found 504.3.

Preparation 59:[(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(a)(2S,5R)-4-{5-[6-(4-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenyl)-2-methyl-pyridin-3-ylcarbamoyl]-pyridin-2-yl}-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

A mixture of[(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (73.0 mg, 0.147 mmol;),(2S,5R)-4-[5-(6-bromo-2-methyl-pyridin-3-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester TFA (91.0 mg, 0.147 mmol; Preparation 58), and 2 Msodium carbonate in water (0.29 mL, 0.588 mmol) DMF (0.9 mL, 10 mmol)was sparged with nitrogen and thentetrakis(triphenylphosphine)palladium(0) (11.9 mg, 0.010 mmol) wasadded. The reaction mixture was purged with nitrogen, heated at 100° C.overnight, cooled, diluted with ethyl acetate (25 mL), washed with water(2×5 mL), dried over magnesium sulfate, filtered, concentrated,dissolved in 1:1 acetic acid:water (5 ml), filtered and purified byreverse phase HPLC. Fractions containing the desired product werecombined and lyophilized to provide the tri-TFA salt of the titleintermediate (100.3 mg) (m/z): [M+H]⁺ calcd for C₄₃H₅₅N₉O₆ 794.46 found794.6.

(b)[(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacidmethyl ester

The product of the previous step was treated with 4 M HCl in 1,4-dioxane(1 mL, 4.0 mmol) for 1 h and the reaction mixture was concentrated byrotary evaporation to give the 4-HCl salt of the title intermediate (75mg, 61% yield). (m/z): [M+H]⁺ calcd for C₃₈H₄₇N₉O₄ 694.38 found 694.6.

Preparation 60:[(S)-1-((S)-2-{4-[6-(4-Amino-2-trifluoromethoxy-phenyl)-pyridin-3-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

(a) 2-Bromo-1-(6-bromo-pyridin-3-yl)-ethanone

A solution of bromine (4 g, 25 mmol) in DCM (10 mL) was added drop wiseover 5 min to a cooled (0° C.) solution of1-(6-bromo-pyridin-3-yl)-ethanone (5 g, 25 mmol) and HBr (48%, 0.2 mL).The cooling bath was removed 40 min later and stirring was continued atRT for 66 h. The solid that formed was filtered, washed with DCM anddried at room temperature to give the impure title intermediate (8.1 g)as a yellow solid. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.96 (m, 1H),8.28-8.25 (m, 1H), 7.82-7.79 (m, 1H), 4.7 (s, 2H).

(b)((S)-1-{(S)-2-[4-(6-Bromo-pyridin-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Following the general procedure of Preparation 29-A, substituting theproduct of step a (7.6 g) for2-bromo-1-(4-bromo-3-methyl-phenyl)-ethanone, the title intermediate wasprepared (3.5 g) as a yellow foam. ¹H NMR (CDCl₃, 400 MHz) δ (ppm):8.73-8.68 (m, 1H), 7.93-7.9 (m, 1H), 7.45-7.43 (m, 1H), 7.25 (s, 1H),5.52-5.49 (m, 1H), 5.24-5.21 (m, 1H), 4.34-4.29 (m, 1H), 3.87-3.81 (m,1H), 3.69 (s, 1H), 2.36-2.31 (m, 1H), 2.29-2.20 (m, 1H), 2.19-2.07 (m,1H), 1.98-1.92 (m, 1H), 1.08-1.01 (m, 1H), 0.92-0.81 (m, 6H).

(c)[4-(5-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-pyridin-2-yl)-3-trifluoromethoxy-phenyl]-carbamicacid tert-butyl ester

A mixture of the product of the previous step (469 mg, 1.04 mmol),[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethoxy-phenyl]-carbamicacid tert-butyl ester (420 mg, 1.04 mmol), Na₂CO₃ (331 mg, 3.12 mmol)and Pd(dppf)Cl₂ (50 mg) in dioxane (9 mL) and water (3 mL) was refluxedfor 5 h. After filtration, the filtrate was concentrated under vacuum togive the crude product (700 m).

(d)[(S)-1-((S)-2-{4-[6-(4-Amino-2-trifluoromethoxy-phenyl)-pyridin-3-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The product of the previous step (700 mg, 1.08 mmol) was dissolved inHCl/dioxane (10 mL) and the mixture was stirred at RT for 3 h. Themixture was concentrated under vacuum to give the residue, which waspurified by preparative HPLC to give the title intermediate (140 mg,yield 24%). ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 9.18 (s, 1H), 8.69-8.67 (m,1H), 8.2-8.15 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 7.02-6.98 (m, 2H), 5.26(m, 1H), 4.23-4.21 (m, 1H), 4.09-4.05 (m, 1H), 3.9-3.88 (m, 1H), 3.65(s, 3H), 2.64-2.5 (m, 1H), 2.38-2.0 (m, 4H), 0.92 (d, J=6.8 Hz, 3H),0.88 (d, J=6.8 Hz, 3H).

Preparation 61:[(S)-2-Methyl-1-((S)-2-{4-[6-(4-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2-trifluoromethoxy-phenyl)-pyridin-3-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

To a mixture of[(S)-1-((S)-2-{5-[6-(4-amino-2-trifluoromethoxy-phenyl)-pyridin-3-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester (140 mg, 0.26 mmol, Preparation 60) in DCM (2.56 mL)and DMA (0.25 mL) was added N,N-diisopropylethylamine (0.14 mL, 0.77mmol) followed by 2-fluoropyridine-5-carbonyl chloride (40.9 mg, 0.26mmol). The reaction mixture was stirred at RT for 1 h and concentrated.

The resulting residue was dissolved in DMSO (0.5 mL) and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (128 mg, 0.64mmol), N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) was added and theresulting mixture was heated at 120° C. overnight. cooled to RT, andpartitioned between EtOAc (10 mL) and water (2 mL). The organic layerwas washed with water (2 mL), dried over sodium sulfate, filtered andconcentrated to give a brownish oil, which was treated with 4 M of HClin 1,4-dioxane (1 mL) at RT for 1 h. The reaction mixture wasconcentrated, dissolved in 1:1 acetic acid:water (7 mL), filtered andpurified by reverse phase prep HPLC to provide the tri-TFA salt of thetitle intermediate as a yellowish solid (57 mg, 20% yield). (m/z):[M+H]⁺ calcd for C₃₇H₄₂F₃N₉O₅ 750.33 found 750.8.

Preparation 62:(R)-4-[5-(4-Bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl

(a) 4-Bromo-2-chloro-5-trifluoromethoxy-phenylamine

To a mixture of 4-bromo-3-trifluoromethoxy-phenylamine (2.0 g, 7.8 mmol)in ACN (60 mL) was slowly added a solution of N-chlorosuccinimide (1.0g, 7.8 mmol) in ACN (40 mL). The reaction mixture was heated at 60° C.overnight and extracted with ethyl actetate/water. The organic layer wasdried over sodium sulfate and purified by flash chromatography (40 gcolumn, 100% hexanes to 10% EtOAc:hexanes) to produce the desiredproduct as an orange-ish colored oil (1.4 g, 64% yield).

(b) N-(4-Bromo-2-chloro-5-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide

To a solution of the product of the previous step (1.2 g, 4.1 mmol) inDCM (5 mL) was slowly added a solution of 2-fluoropyridine-5-carbonylchloride (0.66 g, 4.1 mmol) in DCM (3 mL) and 20 drops of DMA wereadded. The reaction mixture was concentrated to form a yellowish solid(2 g). (m/z): [M+H]⁺ calcd for C₁₃H₆BrClF₄N₂O₂ 412.92, 414.92 found 413,415.

(c)(R)-4-[5-(4-Bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylicacid tert-butyl ester

To a reaction mixture of the product of the previous step (999 mg, 2.42mmol) in a mixture of N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) andDMSO (0.86 mL, 12.08 mmol) was added(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (726 mg, 3.62mmol) and the reaction mixture was heated at 120° C. overnight andextracted with ethyl acetate/water. The organic layer was dried oversodium sulfate and concentrated under vacuum. The dark oil was dissolvedin a small amount of DCM and purified by silica gel chromatography (24 gcolumn, 0-40% ethyl acetate:hexanes) to produce the title intermediateas a white solid (916 mg, 64% yield). (m/z): [M+H]⁺ calcd forC₂₃H₂₅BrClF₃N₄O₄ 593.07, 595.07 found 595.4.

Preparation 63:((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Following the procedure of Preparation 50, the product of Preparation 62(534 mg, 0.9 mmol) was reacted to provide the tri-TFA salt of the titlecompound as a white powder (186 mg, ˜18% yield). (m/z): [M+H]⁺ calcd forC₃₈H₄₂ClF₃N₈O₅ 783.29 found 784.3

Example 1{(S)-1-[(S)-2-(4-{4′-[4-(4-Cyclopropanecarbonyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid(0.015 g, 0.055 mmol) in dichloromethane (2 mL, 30 mmol) were addedN,N-dimethylformamide (0.004 mL, 0.055 mmol) and oxalyl chloride (0.014mL, 0.164 mmol). The reaction mixture was stirred for 25 min and thenN,N-diisopropylethylamine (0.048 mL, 0.273 mmol) was added, followed by((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (0.025 g, 0.055 mmol). The reaction mixture wasstirred for 90 min, dried by rotary evaporation, dissolved in 1:1 aceticacid:water (1.5 mL) and purified by preparative HPLC to provide thetrifluoroacetic acid salt of the title compound (7.9 mg). (m/z): [M+H]⁺calcd for C₄₁H₄₇N₇O₅ 718.36. found 718.2. ¹H NMR (d₆-DMSO, 400 MHz) δ(ppm) 10.07 (s, 1H), 8.09 (s, 1H), 7.90 (dd, J=8.9, 2.1 Hz, 4H), 7.83(dd, J=18.2, 8.5 Hz, 4H), 7.74 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.7 Hz,1H), 7.04 (d, J=9.1 Hz, 2H), 5.11 (t, J=7.1 Hz, 1H), 4.10 (t, J=7.9 Hz,1H), 3.96-3.55 (m, 9H), 3.53 (s, 3H), 3.42-3.22 (m, 4H), 2.45-2.28 (m,1H), 2.20-1.92 (m, 5H), 0.82 (d, J=6.7 Hz, 3H), 0.80-0.69 (m, 6H).

Example 2((S)-1-{(S)-2-[4-(4′-{4-[4-(2,2-Dimethyl-propionyl)-piperazin-1-yl]-benzoylamino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

A reaction mixture of4-[4-(2,2-dimethyl-propionyl)-piperazin-1-yl]-benzoic acid (10.3 mg,0.036 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(8.17 mg, 0.043 mmol), 1-hydroxy-7-azabenzotriazole (6.77 mg, 0.050mmol) in dichloromethane (0.3 mL, 4 mmol) was stirred to dissolution andfor an additional 20 min. Then((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (8.2 mg, 0.018 mmol) and N,N-diisopropylethylamine(7.43 uL, 0.0426 mmol) were added at room temperature. The reactionmixture was stirred overnight, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL) and purified by preparative HPLC to provide thetitle compound as the trifluoroacetic acid salt (5.6 mg). (m/z): [M+H]⁺calcd for C₄₂H₅₁N₇O₅ 734.40 found 734.4.

Example 34-[4-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-ylcarbamoyl)-phenyl]-piperazine-1-carboxylicacid tert-butyl ester

To a solution of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid(24.7 mg, 0.081 mmol) in dichloromethane (0.89 mL, 14 mmol) andN,N-dimethylformamide (0.4 mL, 6 mmol) was addedN,N-diisopropylethylamine (0.071 mL, 0.407 mmol) and methylchloroformate (0.006 mL, 0.081 mmol). The reaction mixture was stirredfor 15 min at room temperature, then((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (25.0 mg, 0.054 mmol) was added and the mixture wasallowed to stir overnight. The reaction mixture was concentrated andthen dissolved in DCM (5 mL) and washed with saturated aqueous sodiumbicarbonate (2 mL). The organic layer was concentrated. Approximately 15mg of the crude material was concentrated, dissolved in 1:1 aceticacid:water (1.5 mL), and purified by preparative HPLC to provide thetrifluoroacetic acid salt of the title compound (7.3 mg). (m/z): [M+H]⁺calcd for C₄₂H₅₁N₇O₆ 750.39 found 750.4.

Example 4{(S)-1-[(S)-2-(4-{4′-[4-(4-Methanesulfonyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

Methylenesulfonyl chloride (1.19 mg, 0.015 mmol) was added to a solutionof[(S)-2-methyl-1-((S)-2-{4-[4′-(4-piperazin-1-yl-benzoylamino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester (10.0 mg, 0.015 mmol) in dichloromethane (0.75 mL, 12mmol), N,N-dimethylacetamide (0.75 mL, 8.1 mmol) and triethylamine (25uL, 0.18 mmol). The reaction mixture was stirred for 15 min at roomtemperature, concentrated by rotary evaporation, dissolved in 1:1 aceticacid:water (1.5 mL) and then purified by preparative HPLC to provide thetrifluoroacetic acid salt of the title compound (12.3 mg). (m/z): [M+H]⁺calcd for C₃₈H₄₅N₇O₆S 728.32 found 728.2.

Example 5((S)-1-{(S)-2-[4-(4′-{[6-(4-Cyclopropanecarbonyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a){(S)-2-Methyl-1-[(S)-2-(4-{4′-[(6-piperazin-1-yl-pyridine-3-carbonyl)-amino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester

Oxalyl chloride (44.0 uL, 0.520 mmol) was added to a solution of4-(5-carboxy-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester(70.3 mg, 0.229 mmol) in dichloromethane (6.67 mL, 104 mmol) andN,N-dimethylformamide (2.01 uL, 0.026 mmol) The reaction mixture wasstirred at room temperature for 20 min and thenN,N-diisopropylethylamine (0.181 mL, 1.04 mmol) was added followed by((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (100.0 mg, 0.217 mmol). The reaction mixture wasstirred for 2 h at room temperature, then dried by rotary evaporation.The crude material was dissolved in dichloromethane (1 mL) and thenwashed with saturated aqueous sodium bicarbonate (1 mL). The organiclayer was concentrated, dissolved in 4.0 M hydrogen chloride in1,4-dioxane (6.7 mL, 27 mmol) and stirred for 1 h at room temperatureuntil completely deprotected. The reaction mixture was concentrated andused directly in the next step.

(b)1-{(S)-2-[4-4′-{[6-(4-Cyclopropanecarbonyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Cyclopropanecarboxylic acid (26.86 mg, 0.312 mmol),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (59.81 mg,0.312 mmol), and 1-hydroxy-7-azabenzotriazole (42.46 mg, 0.312 mmol)were dissolved in N,N-dimethylacetamide (3.868 mL, 41.60 mmol) andstirred for 5 min. Then half of the material from the previous step wasadded to the reaction mixture followed by N,N-diisopropylethylamine(0.269 g, 2.080 mmol. The reaction mixture was stirred overnight at roomtemperature, concentrated by rotary evaporation, dissolved in 1:1 aceticacid:water (1.5 mL) and purified by preparative HPLC to provide thetrifluoroacetic acid salt of the title compound (39.9 mg). (m/z): [M+H]⁺calcd for C₄₀H₄₆N₈O₅ 719.36 found 719.2. ¹H NMR (d₆-DMSO, 400 MHz) δ(ppm) 10.14 (s, 1H), 8.77 (d, J=2.5 Hz, 1H), 8.12 (dd, J=9.7, 3.1 Hz,2H), 7.95-7.78 (m, 6H), 7.75 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.4 Hz, 1H),6.95 (d, J=9.3 Hz, 1H), 5.15-5.07 (m, 1H), 4.15-4.05 (m, 1H), 3.90-3.55(m, 11H), 3.53 (s, 3H), 2.28-2.40 (m, 1H), 2.23-1.87 (m, 5H), 0.75-0.85(m, 3H), 0.79-0.63 (m, 6H).

Example 64-{4-[(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester

A mixture of4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-carboxylicacid (15.0 mg, 0.031 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (11.6 mg, 0.031 mmol) in N,N-dimethylformamide (0.5mL, 6 mmol) was added to 4-(4-aminophenyl)piperazine-1-carboxylic acidtert-butyl ester (28.2 mg, 0.102 mmol) followed byN,N-diisopropylethylamine (10.6 uL, 0.061 mmol). The reaction mixturewas stirred at RT overnight, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL), filtered and purified by preparative HPLC toprovide the trifluoroacetic acid salt of the title compound (26.2 mg).(m/z): [M+H]⁺ calcd for C₄₂H₅₁N₇O₆ 750.39 found 750.4.

Example 7{(S)-1-[(S)-2-(4-{4′-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-phenylcarbamoyl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

(a)[(S)-2-Methyl-1-((S)-2-{4-[4′-(4-piperazin-1-yl-phenylcarbamoyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester

To a solution of[4-{4-[(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (42.4 mg, 0.0565 mmol) in dichloromethane (0.67mL, 10 mmol) was added trifluoroacetic acid (0.3 mL, 0.004 mmol). Thereaction mixture was stirred for 1 h at room temperature, concentrated,dissolved in methanol (1 mL), passed through a Stratospheres™ PL-CO3resin, and the filtrate was concentrated to provide the title compound.(m/z): [M+H]⁺ calcd for C₃₇H₄₃N₇O₄ 650.34 found 650.8.

(b){(S)-1-[(S)-2-(4-{4′-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-phenylcarbamoyl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

Cyclopropanecarboxylic acid (7.30 mg, 0.085 mmol),N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (21.6 mg,0.113 mmol), and 1-hydroxy-7-azabenzotriazole (15.4 mg, 0.113 mmol) werecombined with dichloromethane (0.8 mL, 10 mmol), stirred to dissolutionand then stirred for an additional 20 min. To the reaction mixture wasadded a solution of the product of the previous step in 1:1dichloromethane:N,N-diisopropylethylamine (0.5 mL, 3 mmol) at roomtemperature. The resulting reaction mixture was stirred at RT overnight,concentrated under vacuum, dissolved in 1:1 acetic acid:water (1.5 mL),filtered and purified by preparative HPLC to provide the trifluoroaceticacid salt of the title compound (8.2 mg). (m/z): [M+H]⁺ calcd forC₄₁H₄₇N₇O₅ 718.36 found 718.4.

Example 8{(S)-1-[(S)-2-(4-{4′-[4-(4-cycloproanecarbonyl-piperazin-1-yl)-benzoylamino]-2′-fluoro-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a solution of 4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzoic acid(13 mg, 0.047 mmol) in dichloromethane (1.0 mL, 16 mmol) and one drop ofN,N-dimethylformamide was added oxalyl chloride (0.0119 mL, 0.141 mmol).The reaction mixture was stirred for 25 min and thenN,N-diisopropylethylamine (0.027 mL, 0.16 mmol) was added, followed by((S)-1-{(S)-2-[4-(4′-amino-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (15 mg, 0.031 mmol). The reaction mixture was stirredovernight, concentrated under vacuum, dissolved in 1:1 acetic acid:waterand purified by preparative HPLC to provide the trifluoroacetic acidsalt of the title compound (1.9 mg). (m/z): [M+H]⁺ calcd for C₄₁H₄₆FN₇O₅735.85. found 736.4.

Example 94-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-(4′-{2-[(S)-1-((R)-2-diethylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-benzamide

A combination of (R)-diethylamino-phenyl-acetic acid (6.654 mg, 0.032mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(6.154 mg, 0.032 mmol) and 1-hydroxy-7-azabenzotriazole (4.370 mg, 0.032mmol) in N,N-dimethylacetamide (0.498 mL, 5.350 mmol) was stirred todissolution and then for an additional 20 min.4-(4-Cyclopropanecarbonyl-piperazin-1-yl)-N-[4′-((S)-2-pyrrolidin-2-yl-1H-imidazol-4-yl)-biphenyl-4-yl]-benzamide(15 mg, 0.027 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.134 mmol)were added to the reaction mixture which was stirred at room temperatureovernight. The reaction mixture was then concentrated and dissolved in1:1 acetic acid:water (1.5 mL) and purified by preparative HPLC toprovide the trifluoroacetic acid salt of the title compound to providethe title compound (6.4 mg). (m/z): [M+H]⁺ calcd for C₄₆H₅₁N₇O₃ 750.41.found 750.4.

Example 10((S)-2-Methyl-1-{(S)-2-[4-(4′-{[6-(4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

Half of the crude material from Example 5 step (a) was dissolved inN,N-dimethylformamide (3.22 mL, 41.6 mmol) and N,N-diisopropylethylamine(36.2 uL, 0.208 mmol) and then methyl isocyanate (12.36 uL, 0.208 mmol)was added. The reaction mixture was stirred overnight at roomtemperature, concentrated by rotary evaporation, dissolved in 1:1 aceticacid:water (1.5 mL) and purified by preparative HPLC to provide thetrifluoroacetic acid salt of the title compound (35.7 mg). (m/z): [M+H]⁺calcd for C₃₈H₄₅N₉O₅ 708.35 found 708.2. ¹H NMR (d₆-DMSO, 400 MHz) δ(ppm) 10.13 (s, 1H), 8.75 (d, J=2.6 Hz, 1H), 8.11 (dd, J=8.5, 3.0 Hz,2H), 7.91-7.79 (m, 6H), 7.75 (d, J=8.8 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H),6.95 (d, J=9.1 Hz, 1H), 6.52 (br. s, 1H), 5.15-5.03 (m, 1H), 4.10 (t,J=7.9 Hz, 1H), 3.90-3.75 (m, 3H), 3.66-3.55 (m, 4H), 3.56-3.50 (m, 3H),3.42-3.34 (m, 3H), 2.58 (s, 3H), 1.90-2.25 (m, 1H), 2.18-1.89 (m, 4H),0.81 (d, J=6.8 Hz, 3H), 0.77 (d, J=6.7 Hz, 3H).

Example 11{(S)-1-[(S)-2-(5-Chloro-4-{4′-[4-(4-methylcarbamoyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

The TFA-salt of{(S)-2-methyl-1-[(S)-2-(4-{4′-[4-(4-methylcarbamoyl-piperazin-1-yl)-benzoylamino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamicacid methyl ester (22.0 mg, 0.0311 mmol) was dissolved in methanol (5mL) and treated with Stratospheres™ PL-CO3 resin and stirred for 15 min.The reaction mixture was filtered and the filtrate was concentrated.This crude material was dissolved in N,N-dimethylformamide (1.5 mL, 19mmol) and then N-chlorosuccinimide (6.23 mg, 0.0467 mmol) was added. Thereaction mixture was heated at 50° C. and stirred overnight at 50° C.,concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water(1.5 mL) and purified by preparative HPLC to provide the trifluoroaceticacid salt of the title compound (4.5 mg). (m/z): [M+H]⁺ calcd forC₃₉H₄₅ClN₈O₅ 741.32 found 741.5.

Example 12((S)-1-{(S)-2-[4-(4′-{[6-((R)-4-Cyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

(a)((S)-2-Methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester

A mixture of the hydrochloride salt of{(S)-1-[(S)-2-(5-{4′-[(6-fluoro-pyridine-3-carbonyl)-amino]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester (728.1 mg, 1.17 mmol) [Reactant A] and(R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.352 g,1.76 mmol) [Reactant B] in dimethyl sulfoxide (3.7 mL) andN,N-diisopropylethylamine (1.23 mL, 7.03 mmol) was heated at 120° C.overnight. The reaction mixture was cooled to RT and water (5.0 mL) wasadded. The resulting mixture was centrifuged and filtered. The solid wascombined with the product from a previous reaction in which Reactant A(237.8 mg, 0.383 mmol) was reacted with Reactant B (115.0 mg, 0.574mmol) under the same conditions. The combined solids were dissolved in1:1 acetic acid:water (20 mL), filtered, and split into three equalportions which were purified separately by reverse phase preparativeHPLC. Desired fractions were combined and freeze dried to give a whitesolid. (805.5 mg total).

To the product of the previous step was added 4.0 M hydrogen chloride in1,4-dioxane (6.0 mL, 24 mmol) and the reaction mixture was stirred at RTfor 30 min, and then concentrated. The residue was coevaporated withethyl acetate (3×5.0 mL) and dried under vacuum to give thetri-hydrochloride salt of the title intermediate as a light yellowishsolid (655.9 mg).

(b)((S)-1-{(S)-2-[4-(4′-{[6-((R)-4-Cyclopropanecarbonyl-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Material from the previous step (350 mg) was dissolved inN,N-dimethylacetamide (2.7 mL, 29 mmol) at RT andN,N-diisopropylethylamine (0.52 mL, 3.0 mmol) was added followed bycyclopropanecarbonyl chloride (0.041 mL, 0.45 mmol). The reactionmixture was stirred for 10 min and additional acid chloride was added toconsume all the starting material. The reaction mixture was concentratedand the residue was dissolved in 1:1 acetic acid:water (1.5 mL) andpurified by preparative HPLC. Desired fractions were combined and freezedried to give a white solid.

The white solid was dissolved in ethanol (15.0 mL) at RT and 4.0 Mhydrogen chloride in 1,4-dioxane (6.0 mL) was added. The reactionmixture was stirred for 10 min, and concentrated. The residue wasdissolved in 1:1 acetic acid:water (8 mL), filtered, and purified byreverse phase preparative HPLC. Desired fractions were combined andfreeze dried to give the trifluoroacetic acid salt of the title compoundas a white solid (194.6 mg) (m/z): [M+H]⁺ calcd for C₄₁H₄₈N₈O₅ 733.38found 733.5. ¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.65 (s, 1H), 8.08-8.10(dd, 1H, J=10, 4), 7.67-7.77 (m, 7H), 7.60-7.62 (m, 2H), 6.86-6.88 (d,1H, J=8), 5.13-5.17 (t, 1H, J=15.2), 4.52-4.56 & 4.64-4.68 (m, total1H), 3.99-4.37 (m, 5H), 3.74-3.80 (m, 1H), 3.56 (s, 3H), 2.96-3.00 &3.13-3.23 & 3.38-3.60 (m, total 3H), 2.45-2.52 (m, 1H), 1.91-2.20 (m,4H), 1.09-1.18 (m, 4H), 0.76-0.90 (m, 10H).

Example 13[(S)-1-((S)-2-{4-[4′-({6-[(S)-4-((S)-2,2-Dimethyl-cyclopropane-carbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a mixture of the TFA salt of((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((S)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester (320.0 mg, 0.318 mmol, Preparation 16) and(S)-(+)-2,2-dimethylcyclopropane carboxylic acid (39.9 mg, 0.350 mmol)in N,N-dimethylformamide (30.0 mL, 387.4 mmol) at RT was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.133 g, 0.350 mmol) followed byN,N-diisopropylethylamine (0.277 mL, 1.589 mmol).

The reaction mixture was diluted with water (40.0 mL) and extracted withethyl acetate (2×20.0 mL). Combined organic layers were washed withwater (20.0 mL) and brine (20.0 mL), dried over sodium sulfate, filteredand concentrated to give a yellowish oil. The residue was dissolved in1:1 acetic acid:water (8 mL), filtered and purified by reverse phasepreparative HPLC. Desired fractions were combined and freeze dried.Material was repurified by reverse phase preparative HPLC. Desiredfractions were combined and freeze dried to give the trifluoroaceticacid salt of the title compound as a white solid. (205.1 mg). (m/z):[M+H]⁺ calcd for C₄₃H₅₂N₈O₅ 761.42 found 761.7. ¹H NMR (CD₃OD, 400 MHz)δ (ppm): 8.65 (s, 1H), 8.12-8.15 (m, 1H), 7.67-7.77 (m, 7H), 7.6-7.62(m, 2H), 6.94-6.96 (d, 1H, J=8), 5.13-5.17 (t, 1H, J=16), 4.56-4.65 (m,1H), 4.33-4.36 (m, 1H), 3.99-4.25 (m, 4H), 3.75-3.81 (m, 1H), 3.56 (s,3H), 3.4-3.53 (m, 1H), 3.24-3.3 (m, 1H), 2.95-3.11 (m, 1H), 2.45-2.52(m, 1H), 1.93-2.21 (m, 4H), 1.65-1.71 (m, 1H), 1.16-1.24 (m, 4H),1.00-1.09 (m, 4H), 0.79-0.93 (m, 8H), 0.68-0.71 (m, 1H).

Example 14[(S)-1-((S)-2-{4-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropane-carbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a mixture of the hydrochloride salt of((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester (60.0 mg, 0.0775 mmol) and(S)-(+)-2,2-dimethylcyclopropane carboxylic acid (10.6 mg, 0.093 mmol)in N,N-dimethylformamide (1.5 mL, 19 mmol) at RT was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yOuroniumhexafluorophosphate (35.4 mg, 0.093 mmol) and N,N-diisopropylethylamine(54.0 uL, 0.310 mmol). The reaction mixture was stirred at RT overnight,and then concentrated. The residue was redissolved in 1:1 aceticacid:water (6 mL), filtered and purified by reverse phase preparativeHPLC. Desired fractions were combined and freeze dried to give a whitesolid 34.1 mg). (m/z): [M+H]⁺ calcd for C₄₃H₅₂N₈O₅ 761.42 found 761.7.¹H NMR (CD₃OD, 400 MHz) δ (ppm): 8.76 (s, 1H), 8.18-8.20 (m, 1H),7.76-7.86 (m, 7H), 7.68-7.7 (m, 2H), 6.95-6.99 (m, 1H), 5.22-5.26 (t,1H, J=16), 4.59-4.73 (m, 1H), 4.03-4.38 (m, 5H), 3.82-3.89 (m, 1H),3.69-3.74 (m, 1H), 3.65 (s, 3H), 3.12-3.2 & 3.3-3.5 (m, total 2H),2.53-2.6 (m, 1H), 2.0-2.3 (m, 4H), 1.75-1.78 & 1.82-1.85 (m, total 1H),1.25 (s, 3H), 1.12 (s, 3H), 1.07-1.1 & 1.14-1.17 (m, total 1H), 0.96 (s,3H), 0.88-0.96 & 1.21-1.27 (m, total 6H), 0.76-0.8 (m, 1H).

Example 15[(S)-1-((S)-2-{5-[4′-({6-[(R)-4-((S)-1-Acetyl-2-methyl-pyrrolidine-2-carbonyl)2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-methyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution ofK(S)-2-methyl-1-{(S)-2-[5-(2′-methyl-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester tri-HCl (15 mg, 0.019 mmol; Preparation 18) andN,N-diisopropylethylamine (33.1 uL, 0.190 mmol) dissolved in DMA (0.6mL, 7 mmol) was added (S)-1-acetyl-2-methyl-pyrrolidine-2-carboxylicacid (3.2 mg, 0.019 mmol, Preparation 19) and HATU (11 mg, 0.028 mmol).The reaction mixture was stirred at room temperature overnight,concentrated, dissolved in 1:1 acetic acid:water (4 mL) and purified bypreparative HPLC to provide the di-TFA salt of the title compound (9.1mg). (m/z): [M+H]⁺ calcd for C₄₆H₅₇N₉O₆ 832.44 found 832.4.

Examples 16-20

Following the procedure of Example 15, the intermediate of Preparation19 (20 mg, 0.02 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 16

0.5M (S)-(+)-2,2-dimethyl- cyclopropane carboxylic acid in DMA (38 uL,0.019 mmol) HATU (11 mg, 0.028) 2 TFA salt (11.4 mg) (m/z): [M + H]⁺calcd for C₄₄H₅₄N₈O₅ 775.42 found 775.4 17

cyclopropanecarbonyl chloride (1.7 uL, 0.019 mmol) 2 TFA salt (16.3 mg)(m/z): [M + H]⁺ calcd for C₄₂H₅₀N₈O₅ 747.39 found 747.4 18 NHCH₃ 1Mmethyl isocyanate in toluene 2 TFA salt (14.8 mg) (19 uL, 0.019 mmol)(m/z): [M + H]⁺ calcd for C₄₀H₄₉N₉O₅ 736.39 found 736.4 19

imidazol-4-carboxylic acid (2.1 mg, 0.019 mmol), EDC (5.5 mg, 0.028mmol), and HOAt (3.9 mg, 0.028 mmol) 3 TFA salt (7.6 mg) (m/z): [M + H]⁺calcd for C₄₂H₄₈N₁₀O₅ 773.38 found 773.4 20

(R)-1-acetyl-2-methyl-pyrrolidine- 2-carboxylic acid (3.2 mg, 0.019 mmolHATU (11 mg, 0.028 mmol). 2 TFA salt (12.1 mg) (m/z): [M + H]⁺ calcd forC₄₆H₅₇N₉O₆ 832.44 found 832.4

Example 21[(S)-1-((S)-2-{4-[2′-Ethoxy-4′-({6-[(R)-4-((S)-1-{(S)-2-methoxycarbonylamino-3-methyl-butyryl}-2-methyl-pyrrolidine-2-carbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

The tri-TFA salt of(S)-1-{(S)-2-[4-(2′-ethoxy-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (30 mg, 0.03 mmol; Preparation 22) was dissolved inDMA (1.0 mL, 11 mmol) and N,N-diisopropylethylamine (0.015 mL, 0.086mmol) was added followed by a solution containing 0.5 M(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid in DMA (68.5 uL, 0.034 mmol) and HATU (13.0 mg, 0.034 mmol). Thereaction mixture was stirred at room temperature overnight,concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purifiedby preparative HPLC to provide the di-TFA salt of the title compound(13.5 mg). (m/z): [M+H]⁺ calcd for C₅₂H₆₈N₁₀O₉ 977.52 found 977.6.

Examples 22-24

Following the procedure of Example 21, the intermediate of Preparation22 (30 mg, 0.03 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 22

0.5M (S)-(+)-2,2-dimethyl- cyclopropane carboxylic acid in DMA (69.5 uL,0.034 mmol), HATU (13 mg, 0.034) 2 TFA salt (23.8 mg) (m/z): [M + H]⁺calcd for C₄₅H₅₆N₈O₆ 805.43 found 805.4 23 NHCH₃ 1M methyl isocyanate in2 TFA salt (26.2 mg) toluene (34.2 μL, 0.034 mmol) (m/z): [M + H]⁺ calcdfor C₄₁H₅₁N₉O₆ 766.40 found 766.4 24

imidazol-4-carboxylic acid (3.84 mg, 0.034 mmol), HATU (13 mg, 0.034) 3TFA salt (24 mg) (m/z): [M + H]⁺ calcd for C₄₃H₅₀N₁₀O₆ 803.39 found803.4

Example 25[(S)-1-((S)-2-{5-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethoxy-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester 3[C₂HF₃O₂] (15 mg, 0.014 mmol; Preparation 24) andN,N-diisopropylethylamine (24 uL, 0.14 mmol) dissolved in DMA (0.5 mL, 5mmol) was added 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acidin DMA (28 uL, 0.014 mmol) and HATU (7.8 mg, 0.021 mmol). The reactionmixture was stirred at room temperature overnight, concentrated,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by preparativeHPLC to provide the di-TFA salt of the title compound (11.4 mg). (m/z):[M+H]⁺ calcd for C₄₄H₅₁F₃N₈O₆ 845.39 found 845.4.

Examples 26-28

Following the procedure of Example 25, the intermediate of Preparation24 (15 mg, 0.014 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 26 NHCH₃ 1M methyl isocyanate in toluene 2 TFAsalt (11.7 mg) (14 uL, 0.014 mmol) (m/z): [M + H]⁺ calcd forC₄₀H₄₆F₃N₉O₆ 806.35 found 806.4 27

imidazol-4-carboxylic acid (1.5 mg, 0.014 mmol), EDC (4.0 mg, 0.021mmol), and HOAt (2.8 mg, 0.021 mmol) 3 TFA salt (14.2 mg) (m/z): [M +H]⁺ calcd for C₄₂H₄₅F₃N₁₀O₆ 843.35 found 843.2 28

cyclopropanecarbonyl chloride (1.2 uL, 0.014 mmol) 2 TFA salt (8.8 mg)(m/z): [M + H]⁺ calcd for C₄₂H₄₇F₃N₈O₆ 817.36 found 817.2

Example 29((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of((S)-1-(S)-2-[4-(4′-[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester tri-TFA (11.4 mg, 0.011 mmol; Preparation 28) andN,N-diisopropylethylamine (18 uL, 0.11 mmol) dissolved in DMA (0.4 mL, 4mmol) was added 1.0 M methyl isocyanate in toluene (10 uL, 0.01 mmol).The reaction mixture was stirred at RT overnight, concentrated,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by preparativeHPLC to provide the di-TFA salt of the title compound (7.1 mg). (m/z):[M+H]⁺ calcd for C₄₁H₄₈F₃N₉O₆ 820.37 found 820.5.

Examples 30-33

Following the procedure of Example 29, the intermediate of Preparation28 (11.4 mg, 0.011 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 30

cyclopropanecarbonyl chloride (0.94 uL, 0.01 mmol) 2 TFA salt (9.7 mg)(m/z): [M + H]⁺ calcd for C₄₃H₄₉F₃N₈O₆ 831.37 found 831.2 31

0.5M (S)-2-methyl-pyrrolidine- 1,2-dicarboxylic acid 1-methyl ester inDMA (20.6 uL, 0.0103 mmol) HATU (5.9 mg, 0.0215 mmol). 2 TFA salt (2.9mg) (m/z): [M + H]⁺ calcd for C₄₇H₅₆F₃N₉O₈ 932.42 found 932.4 32

imidazol-4-carboxylic acid (2.1 mg, 0.019 mmol), EDC (3 mg, 0.015 mmol),and HOAt (2.1 mg, 0.015 mmol) 3 TFA salt (12.2 mg) (m/z): [M + H]⁺ calcdfor C₄₃H₄₇F₃N₁₀O₆ 857.36 found 857.2 33

0.5M (S)-(+)-2,2-dimethyl- cyclopropane carboxylic acid in DMA (21 uL,0.010 mmol) HATU (5.9 mg, 0.015) 2 TFA salt (8.2 mg) (m/z): [M + H]⁺calcd for C₄₅H₅₃F₃N₈O₅ 859.40 found 859.4

Example 34[(S)-1-((S)-2-{5-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-2-methyl-1-{(S)-2-[4-(4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester tri-TFA (17 mg, 0.016 mmol; Preparation 25) andN,N-diisopropylethylamine (27.5 uL, 0.158 mmol) dissolved in DMA (0.5mL, 6 mmol) was added 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylicacid in DMA (32 uL, 0.016 mmol) and HATU (9 mg, 0.024 mmol). Thereaction mixture was stirred at room temperature overnight,concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purifiedby preparative HPLC to provide the di-TFA salt of the title compound(8.3 mg). (m/z): [M+H]⁺ calcd for C₄₄H₅₁F₃N₈O₅ 829.39 found 829.4.

Examples 35-38

Following the procedure of Example 34, the intermediate of Preparation25 (17 mg, 0.016 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 35

cyclopropanecarbonyl chloride (1.4 uL, 0.016 mmol) 2 TFA salt (14.1 mg)(m/z): [M + H]⁺ calcd for C₄₂H₄₇F₃N₈O₅ 801.36 found 801.2 36 NHCH₃ 1.0Mmethyl isocyanate in 2 TFA salt (12.3 mg) toluene (16 uL, 0.016 mmol)(m/z): [M + H]⁺ calcd for C₄₀H₄₆F₃N₉O₅ 790.36 found 790.2 37

imidazol-4-carboxylic acid (2 mg, 0.02 mmol), EDC (4.5 mg, 0.024 mmol),and HOAt (3.2 mg, 0.024 mmol) 3 TFA salt (14.4 mg) (m/z): [M + H]⁺ calcdfor C₄₂H₄₅F₃N₁₀O₅ 827.36 found 827.2 38

0.5M (S)-2-methyl-pyrrolidine- 1,2-dicarboxylic acid 1-methyl ester inDMA (31.6 uL, 0.016 mmol) HATU (9 mg, 0.024 mmol). 2 TFA salt (6.8 mg)(m/z): [M + H]⁺ calcd for C₄₆H₅₄F₃N₉O₇ 902.41 found 902.4

Example 39[(S)-1-((S)-2-{4-[4′-({6-[(2R,5S)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2,2′-dimethyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a mixture of (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.39mg, 0.021 mmol) and((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2,2′-dimethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester tri-TFA (20 mg, 0.019 mmol, Preparation 30) in DMF(0.5 mL, 6 mmol) at RT was added HATU (7.98 mg, 0.021 mmol) followed byN,N-diisopropylethylamine (16.60 uL, 0.095 mmol). The reaction mixturewas stirred at RT overnight, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL), filtered, and purified by preparative HPLC toprovide the di-TFA salt of the title compound (15 mg).

(m/z): [M+H]⁺ calcd for C₄₆H₅₈N₈O₅ 803.45 found 803.4.

Example 40

Following the procedure of Example 39, the intermediate of Preparation30 (20 mg, 0.019 mmol) was reacted with(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid (6 mg, 0.021 mmol) to provide the di-TFA salt of the followingcompound (6 mg) (m/z): [M+H]⁺ calcd for C₅₃H₇₀N₁₀O₈ 975.45 found 975.6.

Example 41[(S)-1-((S)-2-{5-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′,6′-difluoro-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(2′,6′-difluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester tri-TFA (20 mg, 0.02 mmol; Preparation 32) andN,N-diisopropylethylamine (33.4 uL, 0.192 mmol) dissolved in DMA (0.6mL, 7 mmol) was added 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylicacid in DMA (38 uL, 0.019 mmol) and HATU (11 mg, 0.029 mmol). Thereaction mixture was stirred at room temperature overnight,concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purifiedby preparative HPLC to provide the di-TFA salt of the title compound(10.1 mg). (m/z): [M+H]⁺ calcd for C₄₃H₅₀F₂N₈O₅ 797.39 found 797.4.

Examples 42-44

Following the procedure of Example 41, the intermediate of Preparation32 (20 mg, 0.02 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 42

cyclopropanecarbonyl chloride (1.7 uL, 0.019 mmol) 2 TFA salt (7.2 mg)(m/z): [M + H]⁺ calcd for C₄₁H₄₄F₂N₈O₅ 769.36 found 769.2 43 NHCH₃ 1Mmethyl isocyanate in toluene 2 TFA salt (4.1 mg) (19 uL, 0.19 mmol(m/z): [M + H]⁺ calcd for C₃₉H₄₅F₂N₉O₅ 758.35 found 758.4 44

imidazol-4-carboxylic acid (2.1 mg, 0.019 mmol), EDC (5.5 mg, 0.029mmol), and HOAt (3.9 mg, 0.029 mmol) 3 TFA salt (5.1 mg) (m/z): [M + H]⁺calcd for C₄₁H₄₄F₂N₁₀O₅ 795.35 found 795.2

Example 45[(S)-1-((S)-2-{5-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-fluoro-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(2′-fluoro-4′-[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester 3[C₂HF₃O₂] (15 mg, 0.015 mmol; Preparation 35) andN,N-diisopropylethylamine (25.5 uL, 0.146 mmol) dissolved in DMA (0.5mL, 5 mmol) was added 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylicacid in DMA (29 uL, 0.015 mmol) and HATU (8.3 mg, 0.022 mmol). Thereaction mixture was stirred at room temperature overnight,concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purifiedby preparative HPLC to provide the di-TFA salt of the title compound(9.5 mg). (m/z): [M+H]⁺ calcd for C₄₃H₅₁FN₈O₅ 779.40 found 779.4.

Examples 46-48

Following the procedure of Example 45, the intermediate of Preparation35 (15 mg, 0.015 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 46

cyclopropanecarbonyl chloride (1.3 uL, 0.015 mmol) 2 TFA salt (12 mg)(m/z): [M + H]⁺ calcd for C₄₁H₄₇FN₈O₅ 751.37 found 751.2 47 NHCH₃ 1Mmethyl isocyanate in toluene 2 TFA salt (10.9 mg) (15 uL, 0.15 mmol)(m/z): [M + H]⁺ calcd for C₃₉H₄₆FN₉O₅ 740.36 found 740.4 48

imidazol-4-carboxylic acid (1.6 mg, 0.015 mmol), EDC (4.2 mg, 0.022mmol), and HOAt (3.0 mg, 0.022 mmol) 3 TFA salt (10.7 mg) (m/z): [M +H]⁺ calcd for C₄₁H₄₅FN₁₀O₅ 777.36 found 777.2

Example 49[(S)-1-((S)-2-{4-[2′-Chloro-4′-({6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

A mixture of6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinicacid (4.54 mg, 0.014 mmol; Preparation 36), HCTU (8.0 mg, 0.019 mmol),N,N-diisopropylethylamine (0.013 mL, 0.072 mmol), and DMA (0.2 mL, 2mmol) was stirred for 30 min at 50° C. and then((S)-1-{(S)-2-[4-(4′-amino-2′-chloro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (7.1 mg, 0.014 mmol; Preparation 37) was added. Thereaction mixture was stirred overnight and then HCTU (8 mg) was addedand the reaction mixture was heated to 55° C. After 5 h, the reactionmixture was cooled to RT, ethyl acetate and water were added. Theorganic layer was concentrated under vacuum and purified by preparativeHPLC to provide the di-TFA salt of the title compound (1.3 mg). (m/z):[M+H]⁺ calcd for C₄₃H₅₁ClN₈O₅ 795.37 found 795.4.

Example 50[(S)-1-((S)-2-{4-[4′-({6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2,2′-difluoro-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacidmethyl ester

To a solution of6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinicacid (6.4 mg, 0.020 mmol; Preparation 36) was added EDC (5.8 mg, 0.030mmol) and HOAt (4.2 mg, 0.030 mmol) in DMA (0.5 mL, 5 mmol). Thereaction mixture was stirred at RT for 30 min and then((S)-1-{(S)-2-[4-(4′-amino-2,2′-difluoro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (10 mg, 0.02 mmol; Preparation 38-B) andN,N-diisopropylethylamine (18 uL, 0.10 mmol) were added and the reactionmixture was stirred at RT overnight. The reaction mixture wasconcentrated by rotary evaporation, dissolved in 1:1 acetic acid:water(1.5 mL) and purified by reverse phase HPLC to provide the di-TFA saltof the title compound (6.8 mg). (m/z): [M+H]⁺ calcd for C₄₃H₅₀F₂N₈O₅797.39 found 797.4.

Example 51[(S)-1-((S)-2-{4-[4′-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]carbamicacid methyl ester

A mixture of (S)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.09 mg,0.018 mmol) and HATU (8.35 mg, 0.022 mmol) was stirred in DMA (1.0 mL,11 mmol) for 10 min. and then((S)-1-{(S)-2-[4-(5′-fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester tri-TFA (20.0 mg, 0.018 mmol, Preparation 41) andN,N-diisopropylethylamine (15.94 uL, 0.091 mmol) were added. Thereaction mixture was stirred at RT overnight, concentrated by rotaryevaporation, dissolved in 1:1 acetic acid:water (1.5 mL), filtered, andpurified by preparative HPLC to provide the di-TFA salt of the titlecompound (4.8 mg). (m/z): [M+H]⁺ calcd for C₄₄H₅₀F₄N₈O₅ 847.38 found847.4.

Example 52

Following the procedure of Example 51, the intermediate of Preparation41 (20 mg, 0.019 mmol) was reacted with(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid (5.24 mg, 0.018 mmol) to provide the di-TFA salt of the followingcompound (2.8 mg) (m/z): [M+H]⁺ calcd for C₅₁H₆₂F₄N₁₀O₈ 1019.47 found1019.4.

Example 53((S)-1-{(S)-2-[4-(5′-Fluoro-4′-{[6-OR)-2-methyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of 1.0 M methyl isocyanate in toluene (11.4 uL, 0.011mmol) dissolved in DMA (0.5 mL), was added((S)-1-{(S)-2-[4-(5′-fluoro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester tri-TFA (12.7 mg, 0.011 mmol; Preparation 44) andN,N-diisopropylethylamine (19.9 uL, 0.114 mmol) and the reaction mixturewas stirred at room temperature overnight, concentrated, dissolved in1:1 acetic acid:water (1.5 mL) and purified by preparative HPLC toprovide the di-TFA salt of the title compound (7.7 mg). (m/z): [M+H]⁺calcd for C₄₀H₄₈F₄N₉O₆ 824.34 found 824.4.

Examples 54-55

Following the procedure of Example 53, the intermediate of Preparation44 (12.7 mg, 0.011 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 54

0.5M (S)-(+)-2,2-dimethyl- cyclopropane carboxylic acid in DMA (22.9 uL,0.011 mmol) HATU (6.5 mg, 0.017) 2 TFA salt (11.8 mg) (m/z): [M + H]⁺calcd for C₄₄H₅₀F₄N₈O₆ 863.38 found 863.4 55

(S)-1-((S)-2-methoxycarbonyl- amino- 3-methyl-butyryl)-2- methyl-pyrrolidine-2-carboxylic acid (3.27 mg, 0.011 mmol) HATU (6.5 mg, 0.017)2 TFA salt (6.7 mg) (m/z): [M + H]⁺ calcd for C₅₁H₆₂F₄N₁₀O₉ 1,035.46found 1035.4

Example 56

To a mixture of4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-carboxylicacid TFA (23.0 mg, 0.033 mmol; Preparation 46) and((S)-1-{(S)-2-[(R)-4-(5-amino-pyridin-2-yl)-3-methyl-piperazine-1-carbonyl]-2-methyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (15.4 mg, 0.033 mmol; Preparation 48) in DMF (0.5 mL)at RT was added HATU (14.0 mg, 0.037 mmol) and N,N-diisopropylethylamine(29.1 μL, 0.167 mmol). The resulting mixture was stirred at RT for 2 h,and then partitioned between EtOAc (10 mL) and water (2 mL). The organiclayer was washed with water (2 mL), dried over sodium sulfate, filteredand concentrated to give a brownish oil. The residue was dissolved in1:1 acetic acid:water (1.5 mL), filtered and purified by reverse phaseHPLC. Desired fractions were combined and freeze dried to give thedi-TFA salt of the title compound (9.1 mg, 22% yield) as a light pinkishsolid. (m/z): [M+H]⁺ calcd for C₅₁H₆₃F₃N₁₀O₉ 1,017.47 found 1017.9.

Example 57[(S)-1-((S)-2-{4-[4′-({6-[(2R),5S)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-5′-fluoro-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester 3-TFA (15 mg, 0.013 mmol; Preparation 50) andN,N-diisopropylethylamine (23 uL, 0.13 mmol) dissolved in DMA (0.5 mL, 5mmol;) was added 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acidin DMA (27 μL, 0.013 mmol) and HATU (7.6 mg, 0.020 mmol). The reactionmixture was stirred at 50° C. for 2 h, concentrated, dissolved in 1:1acetic acid:water (1.5 mL) and purified by reverse phase HPLC to providethe title compound (9.1 mg) as the di-TFA salt. (m/z): [M+H]⁺ calcd forC₄₅H₅₂F₄N₈O₆ 877.39 found 878.0.

Examples 58-60

Following the procedure of Example 57, the intermediate of Preparation50 (15 mg, 0.013 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 58 NHCH₃ 1M methyl isocyanate in toluene 2 TFAsalt (4.5 mg) (13 uL, 0.013 mmol) (m/z): [M + H]⁺ calcd for C₄₁H₄₇F₄N₉O₆838.36 found 839.0 59

imidazol-4-carboxylic acid (1.5 mg, 0.013 mmol), HATU (7.6 mg, 0.020mmol) 3 TFA salt (6.6 mg) (m/z): [M + H]⁺ calcd for C₄₃H₄₆F₄N₁₀O₆ 875.35found 876.0 60

4-pyrazolecarboxylic acid (1.5 mg, 0.013 mmol HATU (7.6 mg, 0.020 mmol)3 TFA salt (6.7 mg) (m/z): [M + H]⁺ calcd for C₄₃H₄₆F₄N₁₀O₆ 875.35 found876.0

Example 61[(S)-1-((S)-2-{4-[5′-Chloro-4′-({6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-2′-trifluoromethyl-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

To a solution of 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acidin DMA (28.9 μL, 0.015 mmol;). and HATU (8.25 mg, 0.022 mmol) dissolvedin DMA (0.5 mL), was added((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester 3 TFA (16 mg, 0.014 mmol; Preparation 53) andN,N-diisopropylethylamine (25.2 uL, 0.15 mmol) and the reaction mixturewas stirred at RT overnight, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL) and purified by reverse phase HPLC to provide thetitle compound (8.6 mg) as the di-TFA salt. (m/z): [M+H]⁺ calcd forC₁₁H₅₀ClF₃N₈O₅ 863.35 found 863.4.

Example 62

Following the procedure of Example 61 the intermediate of Preparation 53(16 mg, 0.014 mmol) was reacted with(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylicacid (4.14 mg, 0.015 mmol) to provide the di-TFA salt of the followingcompound (6.5 mg) (m/z): [M+H]⁺ calcd for C₅₁H₆₂ClF₃N₁₀O₈ 1,035.44 found1035.4.

Example 63-65

Following the procedure of Example 57, substituting the intermediate ofPreparation 55 (15 mg, 0.013 mmol) for the intermediate of Preparation50 (15 mg, 0.013 mmol), the following compounds were prepared

Ex. No. R Reagent Product 63

0.5M (S)-(+)-2,2-dimethyl- cyclopropane carboxylic acid in DMA (27 μL,0.013 mmol) HATU (7.6 mg, 0.02) 2 TFA salt (14.6 mg) (m/z): [M + H]⁺calcd for C₄₅H₅₂ClF₃N₈O₅ 877.37 found 878.0 64 NHCH₃ 1M methylisocyanate in 2 TFA salt (15.3 mg) toluene (m/z): [M + H]⁺ calcd for (13uL, 0.013 mmol) C₄₃H₄₆ClF₃N₁₀O₅ 875.33 found 876.0 65

imidazol-4-carboxylic acid (1.5 mg, 0.013 mmol), HATU (7.6 mg, 0.020mmol) 3 TFA salt (15.3 mg) (m/z): [M + H]⁺ calcd for C₄₃H₄₆ClF₃N₁₀O₅875.33 found 876.0

Example 66

Methoxyacetic acid (1.14 μL, 0.014 mmol) was dissolved in DMA (1 mL) andHATU (5.65 mg, 0.015 mmol) was added. The reaction mixture was stirredat RT for 15 min and then((S)-2-methyl-1-{(S)-2-[4-(4′-{6-[(R)-2-methyl-4-((S)-2-methyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-pyridin-3-ylcarbamoyl}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamicacid methyl ester 3 HCl (12.0 mg, 0.012 mmol; Preparation 57) was addedfollowed by N,N-diisopropylethylamine (10.8 μL, 0.062 mmol) and thereaction mixture was stirred at 55° C. overnight, concentrated,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reversephase HPLC to provide the di-TFA salt of the title compound (8.3 mg)(m/z): [M+H]⁺ calcd for C₄₇H₅₆F₃N₉O₈ 932.42 found 932.4.

Examples 67-70

Following the procedure of Example 66, the intermediate of Preparation57 (12.0 mg, 0.012 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 67

(2S,3S)-3-hydroxy-2- methoxycarbonylamino-butyric acid (2.63 mg, 0.015mmol) HATU (5.65 mg, 0.015 mmol)* 2 TFA salt (1.7 mg) (m/z): [M + H]⁺calcd for C₅₀H₆₁F₃N₁₀O₁₀ 1,019.45 found 1019.4 68

glycolic acid (1.13 mg, 0.015 mmol) HATU (5.65 mg, 0.015 mmol) 2 TFAsalt (1.5 mg) (m/z): [M + H]⁺ calcd for C₄₆H₅₄F₃N₉O₈ 918.41 found 918.469

2-hydroxy-2-methyl-propionic acid (1.55 mg, 0.015 mmol) HATU (5.65 mg,0.015 mmol) 2 TFA salt (0.6 mg) (m/z): [M + H]⁺ calcd for C₄₈H₅₈F₃N₉O₈946.44 found 946.4 70

(S)-2-Methoxycarbonylamino-3,3- dimethyl-butyric acid (2.81 mg, 0.015mmol) HATU (5.65 mg, 0.015 mmol)* 2 TFA salt (1 mg) (m/z): [M + H]⁺calcd for C₅₂H₆₅F₃N₁₀O₉ 1,031.49 found 1031.4 *Prior to isolation andpurification, another equivalent of the corresponding acid, along withHOAt (2.53 mg, 0.019 mmol) and EDC (3.56 mg, 0.019 mmol), previouslystirred at RT for 15 min, were added to the reaction mixture which wasstirred at 60° C. overnight

Example 71{(S)-1-[(S)-2-(4-{4-[5-({6-[(2R,5S)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-6-methyl-pyridin-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

A mixture of (s)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.13 mg,0.019 mmol), and HATU (8.52 mg, 0.022 mmol) was stirred in DMA (1 mL)for 10 min and then[(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester 4 HCl (15 mg, 0.018 mmol; Preparation 59) andN,N-diisopropylethylamine (16.3 μL, 0.093 mmol) were added. The reactionmixture was stirred at RT overnight, concentrated by rotary evaporation,dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reversephase HPLC to provide the tri-TFA salt of the title compound (11 mg).m/z): [M+H]⁺ calcd for C₄₄H₅₅N₉O₅ 790.43 found 790.4.

Examples 72-75

Following the procedure of Example S, the intermediate of Preparation 59(15.0 mg, 0.018 mmol) was reacted with the appropriate reagents toprovide the following compounds:

Ex. No. R Reagent Product 72

(S)-1-((S)-2-methoxycarbonyl- amino-3-methyl-butyryl)-2-methyl-pyrrolidine-2-carboxylic acid (5.35 mg, 0.019 mmol) HATU (8.52mg, 0.022 mmol) 3 TFA salt (1.7 mg) (m/z): [M + H]⁺ calcd forC₅₁H₆₇N₁₁O₈ 962.52 found 962.4 73

cyclopropanecarbonyl chloride (1.95 mg, 0.019 mmol) 3 TFA salt (6.5 mg)(m/z): [M + H]⁺ calcd for C₄₂H₅₁N₉O₅ 762.40 found 762.4 74 NHCH₃methylaminoformyl chloride 3 TFA salt (4 mg) (1.75 mg, 0.019 mmol)(m/z): [M + H]⁺ calcd for C₄₀H₅₀N₁₀O₅ 751.40 found 751.4 75

imidazol-4-carboxylic acid (2.09 mg, 0.019 mmol), EDC (5.37 mg, 0.028mmol) 3 TFA salt (5.4 mg) (m/z): [M + H]⁺ calcd for C₄₂H₄₉N₁₁O₅ 788.39found 788.4

Example 76{(S)-1-[(S)-2-(4-{6-[4-({6-[(R)-4-((S)-2,2-Dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-trifluoromethoxyphenyl]-pyridin-3-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamicacid methyl ester

To a mixture of[(S)-2-methyl-1-((S)-2-{4-[6-(4-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2-trifluoromethoxy-phenyl)-pyridin-3-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamicacid methyl ester 3-TFA (14.25 mg, 0.013 mmol; Preparation 61) and(S)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.2 mg, 0.020 mmol)and HATU (7.4 mg, 0.020 mmol) in DMF (0.5 mL) at RT was addedN,N-diisopropylethylamine (11.37 μL, 0.065 mmol). The reaction mixturewas stirred at RT overnight, concentrated, dissolved in 1:1 aceticacid:water (1.5 mL), and purified by reverse phase HPLC to provide thetri-TFA salt of the title compound (10.8 mg). m/z): [M+H]⁺ calcd forC₄₃H₅₀F₃N₉O₆ 846.38 found 847.0.

Example 77 (a)[(S)-1-((S)-2-{4-[5′-Chloro-2′-trifluoromethoxy-4′-({6-[(R)-2-methyl-4-((S)-2-methyl-pyrrolidine-2-carbonyl)-piperazin-1-yl]-pyridine-3-carbonyl}-amino)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamicacid methyl ester

A mixture of (S)-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (23.2 mg, 0.10 mmol) and HATU (38.5 mg, 0.10 mmol) in DMA (1 mL)was stirred at RT for 20 min and then((S)-1-{(S)-2-[4-(5′-chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester 3TFA (95.0 mg, 0.084 mmol; Preparation 62) was addedfollowed by N,N-diisopropylethylamine (0.074 mL, 0.42 mmol) and thereaction mixture was stirred at 55° C. overnight. The reaction mixturewas diluted in ethyl acetate and washed with water followed by brine.The organic layer was dried over sodium sulfate, filtered andconcentrated to produce a yellow oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane(0.63 mL, 2.53 mmol) and HCl (0.16 mL) and the reaction mixture wasstirred at RT for 1 h, concentrated, and evaporated with EtOAc (2×) toproduce the tri-HCl salt of the title intermediate as a light yellowsolid (87.3 mg).

To the product of the previous step (22 mg, 0.022 mmol) dissolved in DMAwas added 0.5 M methylaminoformyl chloride in DMA (52.6 μL, 0.026 mmol),followed by N,N-diisopropylethylamine (0.016 mL, 0.089 mmol) and thereaction mixture was stirred at RT overnight, concentrated, dissolved in1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC toprovide the di-TFA salt of the title compound (14.4 mg). m/z): [M+H]⁺calcd for C₄₆H₅₄ClF₃N₁₀O₇ 951.38 found 951.6.

Example 78 Alternative synthesis of((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (a)N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowlyadded a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and thereaction mixture was washed with water, brine, and saturated sodiumcarbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43mL) was added to the solid and then water (43 mL) was slowly added. Thereaction mixture was stirred for 1.5 h, filtered, and washed with 1:4ethanol:water (2×25 mL) to give the title intermediate as a white solid(3.87 g). HPLC method C: Retention time=21.3 min.

(b)(2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

The product of the previous step (3.86 g, 10.2 mmol)(2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.62g, 12.2 mmol) and N,N-diisopropylethylamine (5.32 mL, 30.5) wasdissolved in DMSO (12 mL). The reaction mixture heated at 120° C. for 3h, diluted with EtOAc (100 mL), washed with water, and saturated NH₄Cl,water, and brine. The reaction mixture was evaporated to about 40%volume and 3 M HCl in cyclopentyl methyl ether (4.24 mL, 12.7 mmol) wasadded slowly. Seeds from a previous run at smaller scale were added andthe reaction mixture was stirred for 2 days and filtered to provide theHCl salt of the title intermediate (5.15 g, 83% yield). HPLC method C:Retention time=21.1 min

(c)(2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylicacid tert-butyl ester

To a solution of((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester (3.05 g, 6.8 mmol;), bis(pinacolato)diboron (1.81 g,7.1 mmol) and potassium acetate (1.00 g, 10.2 mmol) was added nitrogensparged toluene (15 mL). The resulting mixture was sparged with nitrogenand 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane (Pd catalyst) (0.17 g, 0.204 mmol) was added. Thereaction mixture was stirred at 90° C. overnight.

The reaction mixture was cooled to RT and to this mixture was addednitrogen sparged water (7.6 mL), potassium carbonate (5.16 g, 37.3mmol). The reaction mixture was stirred at 95° C. overnight.

Another portion of the Pd catalyst used above (0.08 g, 0.10 mmol) wasadded to the reaction mixture. After 5 h, the reaction mixture wascooled to RT, diluted with EtOAc (150 mL), washed with water (150 mL)and brine (100 mL), dried over sodium sulfate, and evaporated to give ablack residue (6.7 g), which was purified by silica gel chromatography(eluted with 50-100% EtOAc/hexane) to provide the title intermediate(5.3 g, 90% yield). HPLC method C: Retention time=14.7 min.

(d)((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

Acetyl chloride (2.57 mL, 36.2 mmol) was added to ethanol (18 mL) andstirred at RT for 1 h. To the resulting HCl solution was added asolution of the product of the previous step (3.90 g, 4.5 mmol) inethanol (18 mL). The reaction mixture was warmed to 35° C. and stirredovernight. Acetyl chloride (1.28 mL, 18.1 mmol) was added to ethanol(7.8 mL) and stirred for 30 min. The resulting HCl solution was added tothe reaction mixture at 35° C. The temperature was raised to 40° C. Themixture was concentrated to dryness chased by dichloromethane to providethe crude tri-HCl salt of the title intermediate (5.4 g) which was useddirectly in the next step. HPLC method C: Retention time=10.1 min.

(e)((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamicacid methyl ester

To a solution of the product of the previous step (5.4 g crude, ca. 3.96mmol) and N,N-diisopropylethylamine (6.89 mL, 39.6 mmol) in DCM (52 mL)was slowly added 1 M methylaminoformyl chloride in DMA (4.3 mL). Thereaction mixture stirred at room temperature for 1 h, and then water (50mL) was added. The organic layer was washed with saturated NH₄Cl andthen brine, dried over Na₂SO₄ and evaporated to give 5.2 g crudeproduct, which was purified by silica gel chromatography (133 g silica,2 to 8% methanol/DCM for 15 min then 8% methanol/DCM for 40 min) toprovide the title compound (2.4 g, 74% yield). HPLC method C: Retentiontime 11.2 min.

Using similar synthetic methods, the compounds of Tables 1-34 wereprepared where a blank in any column denotes hydrogen and further whenmore than one variable is listed in a single column, (e.g. Table 5) anyvariable not specified is hydrogen:

TABLE 1

Calc Found Ex. No. R⁵ R¹⁰ Formula [M + H]⁺ [M + H]⁺ 1-1  OCH₃ C₃₉H₄₅N₇O₆708.34 708.2 1-2  OCH₂phenyl C₄₅H₄₉N₇O₆ 784.37 784.2 1-3  CH₃ C₃₈H₄₅N₇O₄664.35 664.2 1-4  CH₂OCH₃ C₄₀H₄₇N₇O₆ 722.36 722.4 1-5 CH((S)-iPr)NHC(O)OCH₃ C₄₄H₅₄N₈O₇ 807.41 807.4 1-6  CH((S)-iPr)N(Et)₂C₄₆H₆₀N₈O₅ 805.47 805.4 1-7  CH((R)-phenyl)NH—C(O)OCH₃ C₄₇H₅₂N₈O₇ 841.4 841.4 1-8  CH((R)-phenyl)N(Et)₂ C₄₉H₅₈N₈O₅ 839.45 839.4 1-9 CH₂N(CH₃)C(O)OtBu C₄₅H₅₆N₈O₇ 821.43 821.4 1-10 CH₂NHC(O)OtBu C₄₄H₅₄N₈O₇807.41 807.0 1-11 CH₂N(CH₃)₂ C₄₁H₅₀N₈O₅ 735.39 735.4 1-12 CH₂NH₂C₃₉H₄₆N₈O₅ 707.36 707.2 1-13 CH₂NHCH₃ C₄₀H₄₈N₈O₅ 721.38 721.4 1-14 CH₂OHC₃₉H₄₅N₇O₆ 708.34 708.2 1-15 NHCH₃ C₃₉H₄₆N₈O₅ 707.36 707.4 1-16 N(CH₃)₂C₄₀H₄₈N₈O₅ 721.38 721.2 1-17

C₄₀H₄₄N₁₀O₅ 745.35 745.4 1-18

C₄₂H₄₅N₇O₆ 744.34 744.2 1-19

C₄₃H₄₆N₈O₅ 755.36 755.4 1-20

C₄₂H₄₅N₇O₆ 744.34 744.2 1-21

C₄₂H₄₅N₉O₅ 756.35 756.4 1-22

C₄₁H₄₅N₉O₅ 744.35 744.2 1-23

C₄₁H₄₄N₈O₆ 745.34 745.2 1-24 NH₂ C₃₈H₄₄N₈O₅ 693.34 693.4 1-25 cPr ClC₄₁H₄₆ClN₇O₅ 752.33 752.2 1-26

C₄₁H₄₈N₈O₆ 749.37 749.2 1-27 CH((S)iPr)NHC(O)OtBu C₄₇H₆₀N₈O₇ 849.46849.4 1-28 CH((S)iPr)NH₂ C₄₂H₅₂N₈O₅ 749.41 749.4 1-29 CH₃ C₃₉H₄₅N₇O₅692.35 692.2 1-30

C₄₂H₅₀N₈O₅ 747.39 747.4 1-31 CH((S)OH)iPr C₄₂H₅₁N₇O₆ 750.39 750.2 1-32

C₄₃H₅₂N₈O₅ 761.41 761.4 1-33 C(CH₃)₂NHCH₃ C₄₂H₅₂N₈O₅ 749.41 749.4 1-34

C₄₁H₄₇N₇O₆ 734.36 734.2 1-35 CH₂iPr C₄₂H₄₉N₇O₅ 732.38 732.4 1-36

C₄₅H₅₄N₈O₅ 787.42 787.4 1-37 CH((R)OH)iPr C₄₂H₅₁N₇O₆ 750.39 750.4 1-38NHiPr C₄₁H₅₀N₈O₅ 735.39 735.4 1-39 O-iPr C₄₁H₄₉N₇O₆ 736.37 736.2 1-40

C₄₂H₅₀N₈O₅ 747.39 747.4 1-41 OCH₂CH₃ C₄₀H₄₇N₇O₆ 722.36 722.2 1-42NHCH₂CH₃ C₄₀H₄₈N₈O₅ 721.38 721.4 1-43 NHCH₂-iPr C₄₂H₅₂N₈O₅ 749.41 749.41-44 cPr CH₃ C₄₂H₄₉N₇O₅ 732.38 732.7 1-45 NHCH₃ CH₃ C₄₀H₄₈N₈O₅ 721.38721.6 1-46

C₄₁H₄₈N₈O₅ 733.38 733.4 1-47 NH-tBu C₄₂H₅₂N₈O₅ 749.41 749.4 1-48

C₄₃H₄₆N₈O₅ 755.36 755.2 1-49 iPr C₄₁H₄₉N₇O₅ 720.38 720.2 1-50

C₄₂H₄₇N₉O₅ 758.37 758.2 1-51

C₄₂H₄₅N₉O₅ 756.35 756.2 1-52

C₄₂H₄₇N₉O₅ 758.37 758.2 1-53

C₄₃H₄₆N₈O₅ 755.36 755.2 1-54

C₄₀H₄₅N₁₁O₅ 760.36 760.2 1-55 CH((S)CH₂OH)NH₂ C₄₀H₄₈N₈O₆ 737.37 737.41-56

C₄₁H₄₅N₉O₅ 744.35 744.2 1-57

C₄₁H₄₅N₉O₅ 744.35 744.2 1-58

C₄₁H₄₈N₈O₅ 733.38 733.2 1-59 CH((S)CH₂OH)NHC(O)OtBu C₄₅H₅₆N₈O₈ 837.42837.4 1-60

Cl C₄₂H₄₄ClN₇O₆ 778.30 778.2 1-61

Cl C₄₂H₄₄ClN₉O₅ 790.32 790.4 1-62 CH((R))cPrNH₂ C₄₂H₅₀N₈O₅ 747.39 747.41-63

C₄₃H₅₀N₈O₆ 775.39 775.4 1-64 CH((R)cPr)NHC(O)CH₃ C₄₄H₅₂N₈O₆ 789.40 789.41-65

C₄₄H₅₂N₈O₆ 789.40 789.4 1-66 CH₂N(CH₃)C(O)CH₃ C₄₂H₅₀N₈O₆ 763.39 763.41-67

C₄₆H₅₆N₈O₇ 833.43 833.4 1-68

C₄₁H₄₈N₈O₅ 733.38 733.4 1-69 CH₂NHC(O)CH₃ Cl C₄₁H₄₇ClN₈O₆ 783.33 783.21-70 tBu Cl C₄₂H₅₀ClN₇O₅ 768.36 768.2 1-71 CH((R)CH₃)NH₂ C₄₀H₄₈N₈O₅721.38 721.2 1-72 CH((R)CH₂OH)NHCH₃ C₄₁H₅₀N₈O₆ 751.39 751.2 1-73CH((R)Pr)NHC(O)CH₃ C₄₄H₅₄N₈O₆ 791.42 791.4 1-74 CH((S)CH₃)NHC(O)OtBuC₄₅H₅₆N₈O₇ 821.43 821.4 1-75 CH((S)CH₃)N(CH₃)C(O)OtBu C₄₆H₅₈N₈O₇ 835.44835.4 1-76 CH((S)iPr) NHC(O)CH₃ C₄₅H₅₆N₈O₆ 805.43 805.4 1-77CH((S)CH₃)NHCH₃ C₄₁H₅₀N₈O₅ 735.39 735.4 1-78 CH((S)CH₃)NH₂ C₄₀H₄₈N₈O₅721.38 721.2 1-79 CH((R)CH₃)N(CH₃)C(O)OtBu C₄₅H₅₆N₈O₇ 821.43 821.4

TABLE 2

Calc Found Ex. No. R⁶ Formula [M + H]⁺ [M + H]⁺ 2-1

C₄₀H₄₅N₉O₆S 780.32 780.4 2-2 NH₂ C₃₇H₄₄N₈O₆S 729.31 729.2 2-3cyclopropyl C₄₀H₄₇N₇O₆S 754.33 754.2 2-4 phenyl C₄₃H₄₇N₇O₆S 790.33 790.2

TABLE 3

Calc Found Ex. No. R^(7a) R^(7b) R^(7c) Formula [M + H]⁺ [M + H]⁺ 3-1 FC₄₁H₄₆FN₇O₅ 736.35 736.4 3-2 OCH₃ C₄₂H₄₉N₇O₆ 748.37 748.4 3-3 F FC₄₁H₄₅F₂N₇O₅ 754.35 754.2 3-4 Cl C₄₁H₄₆ClN₇O₅ 752.33 752.4 3-5 Cl ClC₄₁H₄₅Cl₂N₇O₅ 786.29 786.2 3-6 F C₄₁H₄₆FN₇O₅ 736.35 736.4 3-7 ClC₄₁H₄₆ClN₇O₅ 752.33 752.2

TABLE 4

Calc Found Ex. No. R R¹⁰ Formula [M + H]⁺ [M + H]⁺ 4-1CH((S)-iPr)NHSO₂CH₃ C₄₀H₄₇N₇O₅S 738.34 738.2 4-2 CH((S)-iPr)NHC(O)NHCH₃C₄₁H₄₈N₈O₄ 717.38 717.2 4-3 CH((S)-iPr)N(C₂H₅)₂ C₄₃H₅₃N₇O₃ 716.42 716.44-4 CH((S)-iPr)NHC(O)OtBu C₄₄H₅₃N₇O₅ 760.41 760.4 4-5CH((R)phenyl)NHC(O)OCH₃ C₄₄H₄₅N₇O₅ 752.35 752.2 4-6 CH((S)-iPr)NHC(O)cPrC₄₃H₄₉N₇O₄ 728.38 728.4 4-7 CH((S)-iPr)NH₂ C₃₉H₄₅N₇O₃ 660.36 660.2 4-8CH((R)phenyl)N(C₂H₅)₂ Cl C₄₆H₅₀ClN₇O₃ 784.37 785.2

TABLE 5

Calc Found Ex. No. R⁵ R¹⁰ T R^(8a), R^(8b), R^(9a), R^(9d)* Formula [M +H]⁺ [M + H]⁺ 5-1  OtBu CH C₄₂H₅₁N₇O₆ 750.39 750.4 5-2  cPr Br CHC₄₁H₄₆BrN₇O₅ 796.27 796.2 5-3  OtBu Br CH C₄₂H₅₀BrN₇O₆ 828.30 828.5 5-4 CH₂iPr Br CH C₄₂H₅₀BrN₇O₅ 812.31 812.2 5-5  CH₃ CH C₃₉H₄₅N₇O₅ 692.35692.4 5-6  OtBu N C₄₁H₅₀N₈O₆ 751.39 751.4 5-7  OtBu CH R^(9a)═(S)CH₃C₄₃H₅₃N₇O₆ 764.41 764.4 5-8  OtBu CH R^(9a)═(R)CH₃ C₄₃H₅₃N₇O₆ 764.41764.4 5-9  cPr C R^(8b)═F C₄₁H₄₆FN₇O₅ 736.35 736.4 5-10 OtBu CHR^(9b)═(S)iPr C₄₅H₅₇N₇O₆ 792.44 792.4 5-11 cPr C R^(8b)═OMe C₄₂H₄₉N₇O₆748.37 748.4 5-12 cPr CH R^(9a)═(R)CH₃ C₄₂H₄₉N₇O₅ 732.38 732.4 5-13 cPrCH R^(9a)═(S)CH₃ C₄₂H₄₉N₇O₅ 732.38 732.4 5-14 cPr C R^(8b)═Me C₄₂H₄₉N₇O₅732.38 732.4 5-15 cPr C R^(8b)═Cl C₄₁H₄₆ClN₇O₅ 752.33 752.2 5-16 cPr CHR^(9b)═(S)iPr C₄₄H₅₃N₇O₅ 760.41 760.4 5-17 cPr CH R^(8a)═Me C₄₂H₄₉N₇O₅732.38 732.4 5-18 OtBu C R^(8b)═COOH C₄₃H₅₁N₇O₈ 794.38 794.2 5-19 cPr CHR^(8a)═Cl C₄₁H₄₆ClN₇O₅ 752.33 752.2 5-20 OtBu C R^(8b)═COOMe C₄₄H₅₃N₇O₈808.40 808.2 5-21 cPr H C R^(8b)═CH₂NH₂ C₄₂H₅₀N₈O₅ 747.39 747.4 *R^(8a),R^(9a), R^(9b), R¹⁰ are each H where not specified

TABLE 6

Calc Found Ex. No. R⁵ R^(9a) R^(9b) R^(9c) Formula [M + H]⁺ [M + H]⁺ 6-1OMe C₃₇H₄₃N₉O₆ 710.33 710.2 6-2 cPr C₃₉H₄₅N₉O₅ 720.35 720.2 6-3 NHCH₃C₃₇H₄₄N₁₀O₅ 709.35 710.4 6-4 OtBu (S)CH₃ (R)CH₃ C₄₂H₅₃N₉O₆ 780.41 780.46-5 OtBu (R)CH₃ C₄₁H₅₁N₉O₆ 766.40 766.4 6-6 OtBu C₄₀H₄₉N₉O₆ 752.38 752.46-7 OtBu (S)CH₃ C₄₁H₅₁N₉O₆ 766.40 766.4 6-8 OtBu (R)CH₃ C₄₁H₅₁N₉O₆766.40 766.4 6-9 OtBu (S)CH₃ C₄₁H₅₁N₉O₆ 766.40 766.4

TABLE 7

Calc Found Ex No. R⁵ R^(9a) R^(9b) Formula [M + H]⁺ [M + H]⁺ 7-1  OtBu(R)CH₃ C₄₁H₅₁N₉O₆ 766.4  766.2 7-2  OtBu C₄₀H₄₉N₉O₆ 752.38 752.2 7-3 OtBu (R)CH₃ C₄₁H₅₁N₉O₆ 766.40 766.4 7-4  cPr C₃₉H₄₅N₉O₅ 720.35 720.27-5  Me C₃₇H₄₃N₉O₅ 694.34 694.2 7-6  NHCH₃ C₃₇H₄₄N₁₀O₅ 709.35 709.2 7-7 Me (R)CH₃ C₃₈H₄₅N₉O₅ 708.35 708.2 7-8  cPr (R)CH₃ C₄₀H₄₇N₉O₅ 734.37734.2 7-9  NHCH₃ (R)CH₃ C₃₈H₄₆N₁₀O₅ 723.37 723.4 7-10 cPr (R)CH₃C₄₀H₄₇N₉O₅ 734.37 734.2 7-11 NHCH₃ (R)CH₃ C₃₈H₄₆N₁₀O₅ 723.37 723.4

TABLE 8

Calc Found Ex No. R⁵ R^(7b) Formula [M + H]⁺ [M + H]⁺ 8-1 cPr C₄₀H₄₆N₈O₅719.36 719.2 8-2 Me C₃₈H₄₄N₈O₅ 693.34 693.2 8-3 NHSO₂CH₃ C₃₉H₄₈N₈O₆S757.34 757.2 8-4 OtBu OCH₃ C₄₂H₅₂N₈O₇ 781.40 781.4 8-5 cPr OCH₃C₄₁H₄₈N₈O₆ 749.37 749.2

TABLE 9

Calc Found Ex No. R^(9a) R^(9b) R¹⁰ Formula [M + H]⁺ [M + H]⁺ 9-1 C₄₀H₄₆N₈O₅ 719.36 719.2 9-2  (S)CH₃ C₄₁H₄₈N₈O₅ 733.38 733.2 9-3  (R)CH₃C₄₁H₄₈N₈O₅ 733.38 733.4 9-4  (R)CH₃ C₄₁H₄₈N₈O₅ 733.38 733.4 9-5  (S)CH₃C₄₁H₄₈N₈O₅ 733.38 733.4 9-6  (R)CH₂OH C₄₁H₄₈N₈O₆ 749.37 749.4 9-7 (S)CH₂OH C₄₁H₄₈N₈O₆ 749.37 749.4 9-8  (S)CH₂OH C₄₁H₄₈N₈O₆ 749.37 749.49-9  (R)CH₂OH C₄₁H₄₈N₈O₆ 749.37 749.4 9-10 (R)CH₂OCH₃ C₄₂H₅₀N₈O₆ 763.39763.4 9-11 Cl C₄₀H₄₅ClN₈O₅ 753.32 753.2 9-12 (S)C(O)NH₂ C₄₁H₄₇N₉O₆762.37 762.4 9-13 (R)C(O)NH₂ C₄₁H₄₇N₉O₆ 762.37 762.4 9-14 (S)C(O)N(CH₃)₂C₄₃H₅₁N₉O₆ 790.40 790.4 9-15 (R)C(O)N(CH₃)₂ C₄₃H₅₁N₉O₆ 790.40 790.4

TABLE 10

Ex Calc Found No. R^(9a) R^(9b) R^(9c) R^(9d) R¹⁰ Formula [M + H]⁺ [M +H]⁺ 10-1 C₄₂H₅₀N₈O₅ 747.39 747.4 10-2 (R)CH₃ C₄₃H₅₂N₈O₅ 761.41 762.010-3 (S)CH₃ C₄₃H₅₂N₈O₅ 761.41 761.4 10-4 (S)CH₂OH C₄₃H₅₂N₈O₆ 777.4 789.210-5 (R)CH₂OH C₄₃H₅₂N₈O₆ 777.4 799.4 10-6 (R)CH₂OCH₃ C₄₄H₅₄N₈O₆ 791.42792.4 10-7 (R)CH₃ Cl C₄₃H₅₁ClN₈O₅ 795.37 795.4 10-8 (S)C(O)N(CH₃)₂C₄₅H₅₅N₉O₆ 818.43 818.4 10-9 (R)C(O)N(CH₃)₂ C₄₅H₅₅N₉O₆ 818.43 818.410-10 (S)CH₃ (R)CH₃ C₄₄H₅₄N₈O₅ 775.42 775.4 10-11 (S)CH₃ (R)CH₃C₄₄H₅₄N₈O₅ 775.42 775.4 10-12 (S)CH₃ Cl C₄₃H₅₁ClN₈O₅ 795.37 795.4 10-13(R)CH₂OH C₄₃H₅₂N₈O₆ 777.40 777.3 10-14 (S)CH₂OH C₄₃H₅₂N₈O₆ 777.40 777.410-15 (S)CH₂OCH₃ C₄₄H₅₄N₈O₆ 791.42 791.4 10-16 (R)CH₂OH Cl C₄₃H₅₁ClN₈O₆811.36 811.2 10-17 (S)CH₂OH Cl C₄₃H₅₁ClN₈O₆ 811.36 811.2 10-18 (R)CH₃ EtC₄₅H₅₆N₈O₅ 789.44 789.4 10-19 (S)C₂H₅ C₄₄H₅₄N₈O₅ 775.42 775.4 10-20(R)CH₃ (S)CH₃ C₄₄H₅₄N₈O₅ 775.42 775.4 10-21 (S)CH₃ (R)CH₃ C₄₄H₅₄N₈O₅775.42 775.4 10-22 (a) C₄₉H₆₁N₉O₆ 872.47 872.4 10-23 (R)C₂H₅ C₄₄H₅₄N₈O₅775.42 775.4 10-24 (b) C₅₁H₅₉N₉O₇ 910.45 910.4 10-25 (R)CH₂SCH₃C₄₄H₅₄N₈O₅S 807.39 807.2 10-26 (S)C₂H₅ C₄₄H₅₄N₈O₅ 775.42 776.2 10-27(R)CH₂S(O)₂CH₃ C₄₄H₅₄N₈O₇S 839.38 839.4 10-28 (S)C(O)NH₂ C₄₃H₅₁N₉O₆790.40 790.4 (a) (R)CH₂NH(S)C(O)(1,1-di-methylcyclopropyl) (b)(R)CH₂NHC(O)OCH₂phenyl

TABLE 11

Calc Found Ex No. R^(9a) R^(9b) R^(9c) R^(9d) Formula [M + H]⁺ [M + H]⁺11-1 C₄₁H₅₀N₈O₆ 751.39 751.4 11-2 CH₃ C₄₂H₅₂N₈O₇ 781.40 781.2 11-3(S)CH₃ C₄₂H₅₂N₈O₆ 765.40 765.4 11-4 (R)CH₃ C₄₂H₅₂N₈O₆ 765.40 765.4 11-5(R)CH₃ C₄₂H₅₂N₈O₆ 765.40 765.2 11-6 (S)CH₃ C₄₂H₅₂N₈O₆ 765.40 765.4 11-7(S)CH₂OH C₄₂H₅₂N₈O₇ 781.40 781.7 11-8 (S)CH₂OH C₄₂H₅₂N₈O₇ 781.40 781.411-9 (R)CH₂OH C₄₂H₅₂N₈O₇ 781.40 781.4 11-10 (R)CH₂OCH₃ C₄₃H₅₄N₈O₇ 795.41795.4 11-11* (S)CH₂OH C₄₂H₅₁ClN₈O₇ 815.36 815.6 11-12* (R)CH₂OHC₄₂H₅₁ClN₈O₇ 815.36 815.7 11-13 (S)CONH₂ C₄₂H₅₁N₉O₇ 794.39 795.4 11-14(S)CONH₂ C₄₂H₅₁N₉O₇ 794.39 794.4 11-15 (R)CONH₂ C₄₂H₅₁N₉O₇ 794.39 794.211-16 (R)COOH C₄₂H₅₀N₈O₈ 795.38 795.4 11-17 (S)COOH C₄₂H₅₀N₈O₈ 795.38795.4 11-18 (R)COOH C₄₂H₅₀N₈O₈ 795.38 795.4 11-19 (R)CH₂CH₃ C₄₃H₅₄N₈O₆779.42 779.4 11-20 (S)CH₂CH₃ C₄₃H₅₄N₈O₆ 779.42 779.4 11-21 COOCH₃C₄₃H₅₂N₈O₈ 809.39 809.2 11-22 (R)COOCH₃ C₄₃H₅₂N₈O₈ 809.39 809.4 11-23(S)COOCH₃ C₄₃H₅₂N₈O₈ 809.39 809.4 11-24 (S)CH(CH₃)₂ C₄₄H₅₆N₈O₆ 793.43793.4 11-25 (R)CH(CH₃)₂ C₄₄H₅₆N₈O₆ 793.43 793.4 11-26 (S)CON(CH₃)₂C₄₄H₅₅N₉O₇ 822.42 822.4 11-27 (R)CON(CH₃)₂ C₄₄H₅₅N₉O₇ 822.42 822.4 11-28(S)CH₃ (R)CH₃ C₄₃H₅₄N₈O₆ 779.42 780.0 11-29 (R)CH₃ (S)CH₃ C₄₃H₅₄N₈O₆779.42 780.4 11-30 (R)CH₃ (R)CH₃ C₄₃H₅₄N₈O₆ 779.42 779.4 11-31 (S)CH₃(R)CH₃ C₄₃H₅₄N₈O₆ 779.42 779.4 11-32 (S)CH₃ (R)CH₃ C₄₃H₅₄N₈O₆ 779.42779.4 11-33 (S)C(O)NH₂ C₄₂H₅₁N₉O₇ 794.39 795.4 11-34 (R)C(O)NH₂C₄₂H₅₁N₉O₇ 794.39 794.2 11-35 (S)C(O)NH₂ C₄₂H₅₁N₉O₇ 794.39 794.4 *R¹⁰ isCl; all other R¹⁰ are hydrogen

TABLE 12

Calc Found Ex No. R^(9a) R^(9b) R^(9c) R^(9d) R¹⁰ Formula [M + H]⁺ [M +H]⁺ 12-1 (R)CH₃ C₄₂H₅₂N₈O₅ 749.41 750.4 12-2 (S)CH₃ C₄₂H₅₂N₈O₅ 749.41749.4 12-3 (R)CH₂OH C₄₂H₅₂N₈O₆ 765.40 766.4 12-4 (S)CH₃ (R)CH₃C₄₃H₅₄N₈O₅ 763.42 763.4

TABLE 13

Calc Found Ex No. R^(9a) R^(9b) R^(9d) R¹⁰ Formula [M + H]⁺ [M + H]⁺13-1 C₃₈H₄₅N₉O₅ 708.35 708.2 13-2 CH₃ C₃₉H₄₇N₉O₅ 722.37 722.2 13-3 ClC₃₈H₄₄ClN₉O₅ 742.32 742.2 13-4 (S)CH₃ C₃₉H₄₇N₉O₅ 722.37 722.2 13-5(R)CH₃ C₃₉H₄₇N₉O₅ 722.37 722.4 13-6 (R)CH₃ Cl C₃₉H₄₆ClN₉O₆ 772.33 772.213-7 (R)CH₃ C₃₉H₄₇N₉O₅ 722.37 722.4 13-8 (R)CH₃ Cl C₃₉H₄₆ClN₉O₅ 756.33756.2 13-9 (S)CH₃ C₃₉H₄₇N₉O₅ 722.37 722.2 13-10 (S)CH₃ Cl C₃₉H₄₆ClN₉O₅756.33 756.2 13-11 (R)CH₂OH C₃₉H₄₇N₉O₆ 738.37 738.4 13-12 (S)CH₂OHC₃₉H₄₇N₉O₆ 738.37 738.2 13-13 (S)CH₂OH C₃₉H₄₇N₉O₆ 738.37 738.4 13-14(R)CH₂OH C₃₉H₄₇N₉O₆ 738.37 738.2 13-15 (S)CH₂OCH₃ C₄₀H₄₉N₉O₆ 752.38752.4 13-16 (S)CH₃ (R)CH₃ C₄₀H₄₉N₉O₅ 736.39 736.4

TABLE 14

Calc Found Ex No. R^(9a) R^(9b) R^(9d) Formula [M + H]⁺ [M + H]⁺ 14-1C₄₁H₄₄N₁₀O₅ 757.35 757.4 14-2 (S)CH₃ C₄₂H₄₆N₁₀O₅ 771.37 771.4 14-3(R)CH₃ C₄₂H₄₆N₁₀O₅ 771.37 771.4 14-4 (R)CH₃ C₄₂H₄₆N₁₀O₅ 771.37 771.414-5 (S)CH₃ C₄₂H₄₆N₁₀O₅ 771.37 771.4 14-6 (R)CH₂OH C₄₂H₄₆N₁₀O₆ 787.36787.4 14-7 (S)CH₂OH C₄₂H₄₆N₁₀O₆ 787.36 787.4 14-8 (S)CH₂OH C₄₂H₄₆N₁₀O₆787.36 788.2 14-9 (R)CH₂OH C₄₂H₄₆N₁₀O₆ 787.36 787.4 14-10 (S)CH₂OCH₃C₄₃H₄₈N₁₀O₆ 801.38 801.4 14-11 (S)CH₃ (R)CH₃ C₄₃H₄₈N₁₀O₅ 785.38 785.4

TABLE 15

Calc Found Ex No. R^(9a) R^(9b) R^(9d) Formula [M + H]⁺ [M + H]⁺ 15-1C₄₀H₄₄N₁₀O₅ 745.35 745.4 15-2 (S)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.2 15-3(R)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.4 15-4 (R)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.415-5 (S)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.2 15-6 (R)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36775.4 15-7 (S)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36 775.2 15-8 (S)CH₂OH C₄₁H₄₆N₁₀O₆775.36 775.2 15-9 (R)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36 775.2 15-10 (S)CH₂OCH₃C₄₂H₄₈N₁₀O₆ 789.38 789.4 15-11 (S)CH₃ (R)CH₃ C₄₂H₄₈N₁₀O₅ 773.38 773.4

TABLE 16

Calc Found Ex No. R^(9a) R^(9b) R^(9d) R¹⁰ Formula [M + H]⁺ [M + H]⁺16-1 C₄₀H₄₄N₁₀O₅ 745.35 745.4 16-2 (S)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.4 16-3(R)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.2 16-4 (R)CH₃ C₄₁H₄₆N₁₀O₅ 759.37 759.416-5 (R)CH₃ Cl C₄₁H₄₅ClN₁₀O₅ 793.33 793.4 16-6 (S)CH₃ C₄₁H₄₆N₁₀O₅ 759.37759.4 16-7 (S)CH₃ Cl C₄₁H₄₅ClN₁₀O₅ 793.33 793.2 16-8 (R)CH₂OHC₄₁H₄₆N₁₀O₆ 775.36 775.4 16-9 (S)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36 775.4 16-10(S)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36 775.4 16-11 (R)CH₂OH C₄₁H₄₆N₁₀O₆ 775.36775.4 16-12 (S)CH₂OCH₃ C₄₂H₄₈N₁₀O₆ 789.38 789.4 16-13 (S)CH₃ (R)CH₃C₄₂H₄₈N₁₀O₅ 773.38 773.4

TABLE 17

Ex Calc Found No. R^(9a) R^(9b) R^(9c) R^(9d) Formula [M + H]⁺ [M + H]⁺17-1 C₄₀H₄₇N₉O₆ 750.37 750.3 17-2^((b)) C₄₁H₄₉N₉O₆ 764.38 764.4 17-3(S)CH₃ C₄₁H₄₉N₉O₆ 764.38 764.2 17-4^((a)) (S)CH₃ C₄₁H₄₈ClN₉O₆ 798.34798.2 17-5 (R)CH₃ C₄₁H₄₉N₉O₆ 764.38 764.2 17-6 (R)CH₃ C₄₁H₄₉N₉O₆ 764.38764.8 17-7^((a)) (R)CH₃ C₄₁H₄₈ClN₉O₆ 798.34 798.2 17-8 (S)CH₃ C₄₁H₄₉N₉O₆764.38 764.4 17-9^((a)) (S)CH₃ C₄₁H₄₈ClN₉O₆ 798.34 798.2 17-10 (R)CH₂OHC₄₁H₄₉N₉O₇ 780.38 780.4 17-11 (S)CH₂OH C₄₁H₄₉N₉O₇ 780.38 780.4 17-12(S)CH₂OH C₄₁H₄₉N₉O₇ 780.38 780.4 17-13 (R)CH₂OH C₄₁H₄₉N₉O₇ 780.38 780.417-14 (S)CH₃ (R)CH₃ C₄₂H₄₈N₁₀O₆ 789.38 789.2 17-15 (S)CH₂OCH₃ C₄₂H₅₁N₉O₇794.39 795.4 17-16 (S)CH₃ (R)CH₃ C₄₂H₅₁N₉O₆ 778.4 778.4 17-17 (S)C(O)NH₂C₄₁H₄₈N₁₀O₇ 793.37 793.2 17-18 (R)C(O)NH₂ C₄₁H₄₈N₁₀O₇ 793.37 793.4 17-19(S)CON(CH₃)₂ C₄₃H₅₂N₁₀O₇ 821.4 821.4 17-20 (R)CON(CH₃)₂ C₄₃H₅₂N₁₀O₇821.4 821.4 ^((a))R¹⁰ is Cl ^((b))R¹⁰ is CH₃

TABLE 18

Calc Found Ex No. R^(9a) R^(9b) R^(9d) R¹⁰ Formula [M + H]⁺ [M + H]⁺18-1 C₄₁H₄₆N₁₀O₅ 759.37 759.4 18-2 (S)CH₃ C₄₂H₄₈N₁₀O₅ 773.38 774 18-3(R)CH₃ C₄₂H₄₈N₁₀O₅ 773.38 773.4 18-4 (R)CH₃ C₄₂H₄₈N₁₀O₅ 773.38 774.418-5 (R)CH₃ Cl C₄₂H₄₇ClN₁₀O₅ 807.34 807.2 18-6 (S)CH₃ C₄₂H₄₈N₁₀O₅ 773.38773.4 18-7 (S)CH₃ Cl C₄₂H₄₇ClN₁₀O₅ 807.34 807.4 18-8 (R)CH₂OHC₄₂H₄₈N₁₀O₆ 789.38 789.4 18-9 (S)CH₂OH C₄₂H₄₈N₁₀O₆ 789.38 789.4 18-10(S)CH₂OH C₄₂H₄₈N₁₀O₆ 789.38 789.4 18-11 (S)CH₂OH Cl C₄₂H₄₇ClN₁₀O₆ 823.34823.2 18-12 (R)CH₂OH C₄₂H₄₈N₁₀O₆ 789.38 789.4 18-13 (R)CH₂OH ClC₄₂H₄₇ClN₁₀O₆ 823.34 823.2 18-14 (R)CH₂OCH₃ C₄₃H₅₀N₁₀O₆ 803.39 803.418-15 (S)CH₂OCH₃ C₄₃H₅₀N₁₀O₆ 803.39 803.4 18-16 (S)CH₃ (R)CH₃C₄₃H₅₀N₁₀O₅ 787.40 787.4 18-17 (S)CON(CH₃)₂ C₄₄H₅₁N₁₁O₆ 830.40 830.418-18 (R)CON(CH₃)₂ C₄₄H₅₁N₁₁O₆ 830.40 830.4

TABLE 19

Ex Calc Found No. R^(9a) R^(9b) R^(9c) R^(9d) * Formula [M + H]⁺ [M +H]⁺ 19-1 (R) C₄₃H₅₁N₉O₆ 790.4 790.4 19-2 (S) C₄₃H₅₁N₉O₆ 790.4 790.4 19-3(R)CH₃ (R) C₄₄H₅₃N₉O₆ 804.41 804.4 19-4 (R)CH₃ (R) C₄₄H₅₃N₉O₆ 804.41804.4 19-5 (S)CH₃ (R) C₄₄H₅₃N₉O₆ 804.41 804.4 19-6 (S)CH₂OH (R)C₄₄H₅₃N₉O₇ 820.41 820.4 19-7 (R)CH₂OH (R) C₄₄H₅₃N₉O₇ 820.41 820.4 19-8(R)CH₃ (R)CH₃ (R) C₄₅H₅₅N₉O₆ 818.43 818.4 19-9 (S)CH₃ (R)CH₃ (R)C₄₅H₅₅N₉O₆ 818.43 818.4

TABLE 20

Calc Found Ex No. R R¹⁰ Formula [M + H]⁺ [M + H]⁺ 20-1

C₄₁H₄₉N₉O₆ 764.38 764.2 20-2

C₄₁H₄₈N₈O₆ 749.37 749.6 20-3 CH₂SO₂CH₃ CH₃ C₄₀H₄₈N₈O₇S 785.34 785.2 20-4

C₄₄H₄₆N₁₀O₅ 759.37 759.4 20-5 C(CH₃)₂OH C₄₀H₄₈N₈O₆ 737.37 737.2 20-6CH(CH₂OH)NHC(O)CH₃ C₄₁H₄₉N₉O₇ 780.38 780.2 20-7 CH((R)iPr)NHC(O)CH₃C₄₃H₅₃N₉O₆ 792.41 792.4 20-8 CH((S)CH₃)NHC(O)CH₃ C₄₁H₄₉N₉O₆ 764.38 764.220-9 NHiPr C₄₀H₄₉N₉O₅ 736.39 736.4 20-10

C₄₃H₄₈N₁₀O₅ 785.38 785.4 20-11

C₄₅H₄₆N₁₀O₅ 807.37 807.4 20-12

C₄₄H₄₆N₁₀O₅ 759.37 759.4 20-13

C₄₂H₄₄ClN₉O₅ 790.32 790.2 20-14

C₄₂H₄₄FN₉O₅ 774.35 774.3 20-15

C₄₂H₄₄ClN₉O₅ 790.32 790.2 20-16

C₄₀H₄₃N₉O₅S 762.31 762.2 20-17

C₄₄H₄₆N₁₀O₅ 795.37 795.4 20-18

C₄₀H₄₃N₉O₅S 762.31 762.2 20-19 phenyl C₄₃H₄₆N₈O₅ 755.36 755.4 20-20CH₂SO₂CH₃ C₃₉H₄₆N₈O₇S 771.32 771.2

TABLE 21

Calc Found Ex No. R^(7a), R^(7c) R^(9a,) R^(9b), R^(9c), R^(9d) R⁵Formula [M + H]⁺ [M + H]⁺ 21-1 R^(7a) = CH₃ R^(9a) = (R)CH₃ OtBuC₄₃H₅₄N₈O₆ 779.42 779.4 21-2 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₄H₅₄N₈O₅ 775.42 775.4 21-3 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₂H₅₀N₈O₅ 747.39 747.4 21-4 R^(7a) = CH₃ R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₉N₉O₅ 736.39 736.4 21-5 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₂H₄₈N₁₀O₅ 773.38 773.4 21-6 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-7 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-8 R^(9b) = (S)CH₃, R^(9c) = (R)CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-9 R^(9b) = (S)CH₃, R^(9c) = (R)CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-10 R^(7a) = CH₃, R^(7c) = CH₃ R^(9a) = (R)CH₃NHCH₃ C₄₁H₅₁N₉O₅ 750.40 750.4 21-11 R^(7a) = CH₃, R^(7c) = CH₃ R^(9a) =(R)CH₃

C₄₅H₅₆N₈O₅ 789.44 789.4 21-12 R^(7a) = CH₃, R^(7c) = CH₃ R^(9a) = (R)CH₃

C₄₃H₅₀N₁₀O₅ 787.40 787.4 21-13 R^(7a) = CH₃, R^(7c) = CH₃ R^(9a) =(R)CH₃

C₄₃H₅₂N₈O₅ 761.41 761.4 21-14 R^(7a) = CH₃ R^(9a) = (R)CH₃

C₄₆H₅₇N₉O₇ 848.44 848.4 21-15 R^(7a) = CH₃ R^(9b) = (S)CH₃, R^(9d) =(R)CH₃

C₄₃H₅₀N₁₀O₅ 787.40 787.2 21-16 R^(7a) = CH₃ R^(9b) = (S)CH₃, NHCH₃C₄₁H₅₁N₉O₅ 750.40 750.4 R^(9d) = (R)CH₃ 21-17 R^(7a) = CH₃ R^(9b) =(S)CH₃, R^(9d) = (R)CH₃

C₄₅H₅₆N₈O₅ 789.44 789.4 21-18 R^(7a) = CH₃ R^(9b) = (S)CH₃, R^(9d) =(R)CH₃

C₄₃H₅₂N₈O₅ 761.41 761.4 21-19 R^(7a) = CH₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₇H₅₉N₉O₇ 862.45 862.4 21-20 R^(7a) = CH₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₅H₅₆N₈O₅ 789.44 789.4 21-21 R^(7a) = CH₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₃H₅₂N₈O₅ 761.41 761.4 21-22 R^(7a) = CH₃ R^(9a) = (R)CH₃, NHCH₃C₄₁H₅₁N₉O₅ 750.40 750.4 R^(9d) = (S)CH₃ 21-23 R^(7a) = CH₃ R^(9a) =(R)CH₃, R^(9d) = (S)CH₃

C₄₃H₅₀N₁₀O₅ 787.40 787.4 21-24 R^(7a) = CF₃ R^(9a) = (R)CH₃

C₄₂H₄₇F₃N₈O₅ 801.36 801.2 21-25 R^(7a) = CF₃ R^(9a) = (R)CH₃

C₄₄H₅₁F₃N₈O₅ 829.39 829.4 21-26 R^(7a) = CF₃ R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₆F₃N₉O₅ 790.36 790.2 21-27 R^(7a) = CF₃ R^(9a) = (R)CH₃

C₄₂H₄₅F₃N₁₀O 827.35 827.4 21-28 R^(7a) = CF₃ R^(9a) = (R)CH₃

C₄₆H₅₄F₃N₉O₇ 902.41 902.4 21-29 R^(7a) = CN R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₆N₁₀O₅ 747.37 747.4 21-30 R^(7a) = CN R^(9a) = (R)CH₃

C₄₄H₅₁N₉O₅ 786.40 786.4 21-31 R^(7a) = CN R^(9a) = (R)CH₃

C₄₂H₄₅N₁₁O₅ 784.36 784.4 21-32 R^(7a) = CN R^(9a) = (R)CH₃

C₄₆H₅₄N₁₀O₇ 859.42 859.4 21-33 R^(7a) = CH₃ R^(9a) = (R)CH₂SO₂CH₃

C₄₅H₅₆N₈O₇S 853.40 853.4 21-34 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₄H₅₁F₃N₈O₆ 845.39 845.4 21-35 R^(7a) = OCF₃ R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₆F₃N₉O₆ 806.35 806.4 21-36 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₂H₄₅F₃N₁₀O₆ 843.35 843.2 21-37 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₂H₄₇F₃N₈O₆ 817.36 817.2 21-38 R^(7a) = OCH₃ R^(9a) = (R)CH₃

C₄₆H₅₇N₉O₈ 864.43 864.4 21-39 R^(7a) = OCH₃ R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₉N₉O₆ 752.38 752.4 21-40 R^(7a) = OCH₃ R^(9a) = (R)CH₃

C₄₄H₅₄N₈O₆ 791.42 791.4 21-41 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₆H₅₄F₃N₉O₈ 918.41 918.4 21-42 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₃H₄₈F₃N₉O₇ 860.36 860.4 21-43 R^(7a) = OCF₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₃H₄₉F₃N₈O₆ 831.37 831.2 21-44 R^(7a) = OCF₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₇H₅₆F₃N₉O₈ 932.42 932.4 21-45 R^(7a) = OCF₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₃H₄₇F₃N₁₀O₆ 857.36 857.2 21-46 R^(7a) = OCF₃ R^(9a) = (R)CH₃, R^(9d) =(S)CH₃

C₄₅H₅₃F₃N₈O₆ 859.40 859.4 21-47 R^(7a) = OCF₃ R^(9a) = (R)CH₃, NHCH₃C₄₁H₄₈F₃N₉O₆ 820.37 820.5 R^(9d) = (S)CH₃ 21-48 R^(7a) = OCF₃ R^(9b) =(R)CH₃, R^(9d) = (S)CH₃

C₄₃H₄₉F₃N₈O₆ 831.37 831.4 21-49 R^(7a) = OCF₃ R^(9b) = (R)CH₃, NHCH₃C₄₁H₄₈F₃N₉O₆ 820.37 820.4 R^(9d) = (S)CH₃ 21-50 R^(7a) = OCF₃ R^(9b) =(R)CH₃, R^(9d) = (S)CH₃

C₄₃H₄₇F₃N₁₀O₆ 857.36 857.4 21-51 R^(7a) = OCF₃ R^(9b) = (R)CH₃, R^(9d) =(S)CH₃

C₄₅H₅₃F₃N₈O₆ 859.40 860.2 21-52 R^(7a) = F R^(9a) = (R)CH₃

C₄₁H₄₇FN₈O₅ 751.37 751.2 21-53 R^(7a) = F R^(9a) = (R)CH₃ NHCH₃C₃₉H₄₆FN₉O₅ 740.36 740.4 21-54 R^(7a) = F R^(9a) = (R)CH₃

C₄₁H₄₅FN₁₀O₅ 777.36 777.2 21-55 R^(7a) = F R^(9a) = (R)CH₃

C₄₃H₅₁FN₈O₅ 779.40 779.4 21-56 R^(7a) = F, R^(7c) = F R^(9a) = (R)CH₃

C₄₁H₄₆F₂N₈O₅ 769.36 769.2 21-57 R^(7a) = F, R^(7c) = F R^(9a) = (R)CH₃

C₄₃H₅₀F₂N₈O₅ 797.39 797.4 21-58 R^(7a) = F, R^(7c) = F R^(9a) = (R)CH₃NHCH₃ C₃₉H₄₅F₂N₉O₅ 758.35 758.4 21-59 R^(7a) = F, R^(7c) = F R^(9a) =(R)CH₃

C₄₁H₄₄F₂N₁₀O₅ 795.35 795.2 21-60

C₄₅H₅₃N₉O₆ 816.41 816.4 21-61

C₄₇H₅₇N₉O₆ 844.44 844.4 21-62

C₄₄H₅₃N₉O₆ 804.41 804.4 21-63

C₄₄H₅₃N₉O₆ 804.41 804.2 21-64

C₄₆H₅₅N₉O₆ 830.43 830.4 21-65

C₄₈H₅₉N₉O₆ 858.46 858.4 21-66 R^(9a) = (S)CH₃

C₄₅H₅₅N₉O₆ 818.43 818.4 21-67 R^(9b) = (S)CH₂OCH₃

C₄₆H₅₇N₉O₇ 848.44 848.4 21-68 R^(9b) = (R)CH₂OH

C₄₅H₅₅N₉O₇ 834.42 834.4 21-69 R^(9b) = (S)CH₂OH

C₄₅H₅₅N₉O₇ 834.42 834.4 21-70 R^(9a) = (R)CH₃

C₄₅H₅₅N₉O₆ 818.43 818.4 21-71

C₄₃H₅₀FN₉O₆ 808.39 808.4 21-72 R^(9a) = (R)CH₃

C₄₅H₅₅N₉O₇ 834.42 834.4 21-73 R^(9a) = (R)CH₂CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-74 R^(9a) = (S)CH₂CH₃

C₄₆H₅₇N₉O₆ 832.44 832.4 21-75 R^(9a) = (R)CH₃ (b) C₅₀H₆₄N₁₀O₈ 933.49933.4 21-76 R^(9a) = (R)CH₃ (a) C₅₀H₆₄N₁₀O₈ 933.49 933.4 21-77 R^(7a) =OCH₃ R^(9a) = (R)CH₃ (a) C₅₁H₆₆N₁₀O₉ 963.50 963.4

TABLE 22

Calc Found Ex No. R¹ R^(9a) R⁵ Formula [M + H]⁺ [M + H]⁺ 22-1 (S)CH₃

C₃₈H₄₂N₈O₅ 691.33 691.2 22-2 (S)CH₂OH

C₃₈H₄₂N₈O₆ 707.32 707.7 22-3 (S)C(CH₃)₂OH

C₄₀H₄₆N₈O₆ 735.35 735.2 22-4 (R)phenyl

C₄₃H₄₄N₈O₅ 753.34 753.2 22-5 (S)CH₂((S)CH₃)OCH₃

C₄₀H₄₆N₈O₆ 735.35 735.2 22-6 (S)CH₃ (R)CH₃

C₄₁H₄₈N₈O₅ 733.38 733.4 22-7 (S)CH₂OH (R)CH₃

C₄₁H₄₈N₈O₆ 749.37 749.4 22-8 (R)phenyl (R)CH₃

C₄₆H₅₀N₈O₅ 795.39 795.4 22-9 (S)CH₂((S)CH₃)OCH₃ (R)CH₃

C₄₃H₅₂N₈O₆ 777.40 777.4 22-10 (S)C(CH₃)₃ (R)CH₃

C₄₄H₅₄N₈O₅ 775.42 775.4 22-11 (S)cPr (R)CH₃

C₄₃H₅₀N₈O₅ 759.39 759.4 22-12 (R)CH(CH₃)₂ (R)CH₃

C₄₃H₅₂N₈O₅ 761.41 761.4

TABLE 23

Calc Found Ex No. R^(7a), R^(7c) R^(9a), R^(9b), R^(9d) R⁵ Formula [M +H]⁺ [M + H]⁺ 23-1 R^(9a) = (R)CH₃

C₄₃H₅₂N₈O₅ 761.41 761.7 23-2 R^(9a) = (R)CH₃

C₄₄H₅₆N₈O₆ 793.43 793.4 23-3 R^(9a) = (R)CH₃

C₄₁H₄₆N₁₀O₅ 759.37 759.4 23-4 R^(9a) = (R)CH₃

C₄₅H₅₅N₉O₇ 834.42 834.4 23-5 R^(9a) = (R)CH₃ NHCH₃ C₃₉H₄₇N₉O₅ 722.37722.4 23-6 R^(9a) = (R)CH₃

C₄₄H₅₄N₈O₅ 775.42 775.4 23-7 R^(9a) = (R)CH₃ R^(9d) = (S)CH₃

C₄₂H₄₈N₁₀O₅ 773.38 773.4 23-8 R^(9a) = (R)CH₃ (a) C₅₁H₆₆N₁₀O₈ 947.51947.6 R^(9d) = (S)CH₃ 23-9 R^(9a) = (R)CH₃ NHCH₃ C₄₀H₄₉N₉O₅ 736.39 736.4R^(9d) = (S)CH₃ 23-10 R^(9a) = (R)CH₃ (a) C₅₀H₆₄N₁₀O₈ 933.49 933.4 23-11R^(7a) = OCH₃ R^(9a) = (R)CH₃

C₄₄H₅₄N₈O₆ 791.42 791.4 23-12 R^(7a) = CH₃ R^(9a) = (R)CH₃ NHCH₃C₄₀H₄₉N₉O₃ 736.39 736.4 23-13 R^(7a) = OCF₃ R^(9a) = (R)CH₃

C₄₄H₅₁F₃N₈O₆ 845.39 845.8 23-14 R^(7a) = OCF₃ R^(9a) = (R)CH₃ (a)C₅₁H₆₃F₃N₁₀O₉ 1017.47 1017.9

TABLE 24

Ex R^(11a) R^(11b) R^(7a) R^(7b) R^(7c) Calc Found No. R^(11c) R^(11d)R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 24-1

C₄₆H₅₅N₉O₇ 846.42 846.4 24-2

C₄₆H₅₅N₉O₆ 830.43 830.4 24-3

C₅₁H₆₄N₁₀O₈ 945.49 945.4 24-4

C₄₇H₆₀N₁₀O₆ 861.47 861.4 24-5

C₄₉H₆₂N₁₀O₇ 903.48 903.4 24-6

C₅₁H₆₆N₁₀O₈ 947.51 945.4 24-7

C₄₃H₅₂N₈O₅ 761.41 761.4 24-8

C₄₉H₆₂N₁₀O₈ 919.48 919.6 24-9

C₄₃H₅₃N₉O₅ 776.42 776.4 24-10 CH₂t-Bu C₄₃H₅₄N₈O₅ 763.42 763.4 24-11

C₄₁H₄₉N₉O₅ 748.39 748.4 24-12 NHC(CH₃)₂CH₂OH C₄₂H₅₃N₉O₆ 780.41 780.424-13

C₄₇H₅₇N₉O₈ 876.43 876.4 24-14

C₄₃H₅₂N₈O₆ 777.4 777.4 24-15 R^(7a) = OiPr NHCH₃ C₄₂H₅₃N₉O₆ 780.41 780.424-16

C₄₇H₆₀N₁₀O₆ 861.47 861.6 24-17

C₄₇H₆₀N₁₀O₇ 877.47 877.4 24-18

C₄₈H₆₂N₁₀O₆ 875.49 875.6 24-19

C₄₉H₆₂N₁₀O₈ 919.48 919.4 24-20 R^(11b) = CH₃

C₄₆H₅₅N₉O₆ 830.43 830.7 24-21

C₄₃H₅₃N₉O₅ 776.42 776.4 24-22 R^(7a) = OCHF₂ NHCH₃ C₄₀H₄₇F₂N₉O₆ 788.36788.4 24-23 R^(11b) = OCF₃ NHCH₃ C₄₀H₄₆F₃N₉O₆ 806.35 806.4 24-24 R^(7a)= CH₃ NHCH₃ C₄₀H₄₈FN₉O₅ 754.38 754.8 R^(7d) = F 24-25 R^(7a) = OCH₃R^(7d) = Cl

C₄₂H₄₉ClN₈O₆ 797.35 798.0 24-26 R^(7b) = OH NHCH₃ C₃₉H₄₇N₉O₆ 738.37738.8 24-27 R^(7b) = CH₂CH₃

C₄₃H₅₀N₁₀O₅ 787.4 787.8 24-28 R^(7b) = CH₂CH₃ NHCH₃ C₄₁H₅₁N₉O₅ 750.4750.8 24-29 R^(7a) = Cl R^(7b) = F

C₄₁H₄₄ClFN₁₀O₅ 811.32 811.6 24-30 R^(7a) = Cl R^(7b) = F NHCH₃C₃₉H₄₅ClFN₉O₅ 774.32 774.8 24-31 R^(7a) = Cl R^(7b) = F

C₄₃H₅₀ClFN₈O₅ 813.36 813.6 24-32 R^(7a) = Cl R^(7b) = F

C₅₀H₆₂ClFN₁₀O₈ 985.44 985.6 24-33 R^(7a) = OCH₃ R^(7c) = OCH₃

C₄₈H₆₁N₉O₉ 908.46 907.8

TABLE 25

Calc Found Ex No. R^(11a) R^(11b) R^(11c) R^(11d) R^(7a) R^(7b) R^(7c)R^(7d) Formula [M + H]⁺ [M + H]⁺ 25-1  R^(7a) = CF₃ C₅₁H₆₃F₃N₁₀O₈1,001.48 1001.4 25-2  R^(7a) = CN C₅₁H₆₃N₁₁O₈ 958.49 958.4 25-3  R^(11b)= CH₃ C₅₁H₆₆N₁₀O₈ 947.51 947.8 25-4  R^(7a) = CH₃ C₅₁H₆₆N₁₀O₈ 947.51947.4 25-5  R^(7a) = O(CH₂)₂OCH₃ C₅₃H₇₀N₁₀O₁₀ 1,007.53 1007.4 25-6 R^(7a) = OiPr C₅₃H₇₀N₁₀O₉ 991.53 991.6 25-7  R^(11b) = F C₅₀H₆₃FN₁₀O₈951.48 951.4 25-8  R^(11b) = CF₃ C₅₁H₆₃F₃N₁₀O₈ 1,001.48 1001.4 25-9 R^(7b) = F R^(7d) = F C₅₀H₆₂F₂N₁₀O₈ 969.47 969.4 25-10 R^(11b) = OCH₃C₅₁H₆₆N₁₀O₉ 963.5 963.4 25-11 R^(11b) = F R^(7a) = F C₅₀H₆₂F₂N₁₀O₈969.47 969.6 25-12 R^(7a) = CH₃ R^(7c) = CH₃ C₅₂H₆₈N₁₀O₈ 961.52 961.625-13 R^(7a) = Cl C₅₀H₆₃ClN₁₀O₈ 967.45 967.4 25-14 R^(7a) = F R^(7c) = FC₅₀H₆₂F₂N₁₀O₈ 969.47 969.4 25-15 R^(11b) = OCF₃ C₅₁H₆₃F₃N₁₀O₉ 1,017.471017.4 25-16 R^(11a) = CH₃ R^(7c) = F C₅₁H₆₅FN₁₀O₈ 965.5 965.4 25-17R^(11b) = CF₃ R^(7a) = F C₅₁H₆₂F₄N₁₀O₈ 1,019.47 1019.4 25-18 R^(7b) =OCH₃ C₅₁H₆₆N₁₀O₉ 963.5 963.4 25-19 R^(7b) = CF₃ C₅₁H₆₃F₃N₁₀O₈ 1,001.481001.4 25-20 R^(11a) = CH₃ C₅₁H₆₆N₁₀O₈ 947.51 947.6 25-21 R^(7b) = FC₅₀H₆₃FN₁₀O₈ 951.48 951.4 25-22 R^(7b) = Cl C₅₀H₆₃ClN₁₀O₈ 967.45 967.625-23 R^(11b) = OCHF₂ C₅₁H₆₄F₂N₁₀O₉ 999.48 999.6 25-24 R^(7a) = CF₃R^(7b) = F C₅₁H₆₂F₄N₁₀O₈ 1,019.47 1019.4 25-25 R^(7a) = OCF₃ R^(7b) = FC₅₁H₆₂F₄N₁₀O₉ 1,035.46 1035.4 25-26 R^(11b) = CH₃ R^(7a) = FC₅₁H₆₅FN₁₀O₈ 965.5 965.4 25-27 R^(11a) = CF₃ C₅₁H₆₃F₃N₁₀O₈ 1,001.481001.4 25-28 R^(11a) = F C₅₀H₆₃FN₁₀O₈ 951.48 951.4 25-29 R^(11a) = OCF₃C₅₁H₆₃F₃N₁₀O₉ 1,017.47 1017.4 25-30 R^(7b) = CN C₅₁H₆₃N₁₁O₈ 958.49 958.425-31 R^(7a) = Cl R^(7d) = OCH₃ C₅₁H₆₅ClN₁₀O₉ 997.46 997.6 25-32 R^(11b)= CH₃ R^(7a) = F R^(7c) = F C₅₁H₆₄F₂N₁₀O₈ 983.49 983.4 25-33 R^(7a) = FR^(7d) = F C₅₀H₆₂F₂N₁₀O₈ 969.47 969.6 25-34 R^(7a) = Cl R^(7d) = FC₅₀H₆₂ClFN₁₀O₈ 985.44 985.4 25-35 R^(7a) = CH₃ R^(7d) = F C₅₁H₆₅FN₁₀O₈965.5 965.6 25-36 R^(7a) = OCH₃ R^(7d) = Cl C₅₁H₆₅ClN₁₀O₉ 997.46 998.225-37 R^(7b) = OH C₅₀H₆₄N₁₀O₉ 949.49 950.2 25-38 R^(7a) = OCH₃ R^(7c) =OCH₃ C₅₂H₆₈N₁₀O₁₀ 993.51 994.2 25-39 R^(7a) = F R^(7b) = F C₅₀H₆₂F₂N₁₀O₈969.47 969.4 25-40 R^(7a) = F R^(7d) = Cl C₅₀H₆₂ClFN₁₀O₈ 985.44 985.425-41 R^(7b) = CH₂CH₃ C₅₂H₆₈N₁₀O₈ 961.52 961.6

TABLE 26

Ex. Calc Found No. R^(11a) R^(11b) R^(11c) R^(11d) R^(7a) R^(7b) R^(7c)R^(7d) Formula [M + H]⁺ [M + H]⁺ 26-1  R^(11b) = CH₃ C₄₄H₅₄N₈O₅ 775.42775.4 26-2  R^(7a) = O(CH₂)₂OCH₃ C₄₆H₅₈N₈O₇ 835.44 835.4 26-3  R^(7a) =OiPr C₄₆H₅₈N₈O₆ 819.45 819.4 26-4  R^(11b) = F C₄₃H₅₁FN₈O₅ 779.4 779.426-5  R^(7b) = F R^(7d) = F C₄₃H₅₀F₂N₈O₅ 797.39 797.4 26-6  R^(11b) =OCH₃ C₄₄H₅₄N₈O₆ 791.42 791.4 26-7  R^(11b) = CF₃ R^(7a) = F C₄₄H₅₀F₄N₈O₅847.38 847.4 26-8  R^(11b) = CF₃ C₄₄H₅₁F₃N₈O₅ 829.39 829.6 26-9  R^(11a)= CH₃ R^(7c) = F C₄₄H₅₃FN₈O₅ 793.41 793.4 26-10 R^(11b) = OCF₃C₄₄H₅₁F₃N₈O₆ 845.39 845.0 26-11 R^(7b) = OCH₃ C₄₄H₅₄N₈O₆ 791.42 791.426-12 R^(7b) = CF₃ C₄₄H₅₁F₃N₈O₅ 829.39 829.4 26-13 R^(11a) = CH₃C₄₄H₅₄N₈O₅ 775.42 775.4 26-14 R^(7b) = F C₄₃H₅₁FN₈O₅ 779.4 779.4 26-15R^(7b) = Cl C₄₃H₅₁ClN₈O₅ 795.37 795.4 26-16 R^(7b) = OCHF₂ C₄₄H₅₂F₂N₈O₆827.4 827.4 26-17 R^(11a) = CF₃ C₄₄H₅₁F₃N₈O₅ 829.39 829.4 26-18 R^(11a)= OCF₃ C₄₄H₅₁F₃N₈O₆ 845.39 845.4 26-19 R^(11a) = F C₄₃H₅₁FN₈O₅ 779.4779.4 26-20 R^(7a) = CF₃ R^(7b) = F C₄₄H₅₀F₄N₈O₅ 847.38 847.4 26-21R^(7a) = OCF₃ R^(7b) = F C₄₄H₅₀F₄N₈O₆ 863.38 863.4 26-22 R^(7b) = CNC₄₄H₅₁N₉O₅ 786.4 786.4 26-23 R^(7a) = Cl R^(7d) = OCH₃ C₄₄H₅₃ClN₈O₆825.38 825.4 26-24 R^(11b) = CH₃ R^(7a) = F C₄₄H₅₃FN₈O₅ 793.41 793.026-25 R^(11b) = CH₃ R^(7a) = F R^(7c) = F C₄₄H₅₂F₂N₈O₅ 811.4 811.4 26-26R^(7a) = F R^(7d) = F C₄₃H₅₀F₂N₈O₅ 797.39 797.4 26-27 R^(7a) = Cl R^(7d)= F C₄₃H₅₀ClFN₈O₅ 813.36 813.4 26-28 R^(7a) = F R^(7b) = F C₄₃H₅₀F₂N₈O₅797.39 797.4 26-29 R^(7a) = F R^(7d) = Cl C₄₃H₅₀ClFN₈O₅ 813.36 813.426-30 R^(7a) = CH₃ R^(7d) = F C₄₄H₅₃FN₈O₅ 793.41 793.8 26-31 R^(7a) =OCH₃ R^(7d) = Cl C₄₄H₅₃ClN₈O₆ 825.38 826.0 26-32 R^(7b) = OH C₄₃H₅₂N₈O₆777.4 778.0 26-33 R^(7a) = OCH₃ R^(7c) = OCH₃ C₄₅H₅₆N₈O₇ 821.43 822.026-34 R^(7b) = CH₂CH₃ C₄₅H₅₆N₈O₅ 789.44 789.8

TABLE 27

Calc Found Ex No. R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 27-1 

C₅₁H₆₃F₃N₁₀O₉ 1,017.47 1017.4 27-2  NH(CH₂)₂OCH₃ C₄₂H₅₀F₃N₉O₇ 850.38850.4 27-3 

C₄₃H₅₂F₃N₉O₆ 848.40 848.4 27-4 

C₄₂H₅₀F₃N₉O₆ 834.38 834.4 27-5  t-Bu C₄₃H₅₁F₃N₈O₆ 833.39 833.4 27-6 

C₄₂H₄₈F₃N₉O₆ 832.37 832.4 27-7 

C₄₃H₄₇F₃N₁₀O₆ 857.36 857.4 27-8  F

C₄₉H₅₉F₄N₉O₈ 978.44 977.6 27-9  F

C₄₄H₅₁F₄N₉O₆ 878.39 877.8 27-10

C₄₄H₅₀F₃N₉O₆ 858.38 857.6 27-11

C₄₃H₄₇F₃N₁₀O₆ 857.36 856.6 27-12

C₄₅H₅₂F₃N₉O₈ 904.39 903.6 27-13 O(CH₂)₂OCH₃ C₄₂H₄₉F₃N₈O₈ 851.36 850.627-14

C₄₃H₄₉F₃N₈O₆ 831.37 830.6 27-15

C₄₈H₅₉F₃N₁₀O₈ 961.45 961.6 27-16

C₄₇H₅₆F₃N₉O₈ 932.42 932.6 27-17

C₄₈H₅₉F₃N₁₀O₇ 945.45 945.6 27-18

C₄₈H₅₉F₃N₁₀O₇ 945.45 945.6 27-19

C₄₆H₅₅F₃N₁₀O₇ 917.42 917.6 27-20

C₄₈H₅₈F₃N₉O₉ 962.43 962.6 27-21

C₄₈H₅₈F₃N₉O₈ 946.44 946.6 27-22

C₄₉H₆₁F₃N₁₀O₇ 959.47 959.6 27-23

C₄₈H₅₇F₃N₁₀O₇ 943.44 943.6 27-24

C₄₄H₅₀F₃N₉O₆ 858.38 858.6 27-25

C₄₆H₅₆F₃N₉O₈ 920.42 920.6 27-26

C₄₅H₅₄F₃N₉O₆ 874.42 874.6 27-27

C₄₆H₅₆F₃N₉O₈ 920.42 920.6 27-28 OCH₃

C₅₂H₆₅F₃N₁₀O₁₀ 1,047.48 1046.6 27-29 OCH₃

C₄₃H₄₇F₃N₁₀O₇ 873.36 872.6 27-30 OCH₃

C₄₅H₅₃F₃N₈O₇ 875.4 874.6 27-31 OCH₃

C₄₈H₅₈F₃N₉O₉ 962.43 961.6 27-32 OCH₃ NHCH₃ C₄₁H₄₈F₃N₉O₇ 836.36 835.827-33 F

C₄₂H₄₄F₄N₁₀O₆ 861.34 862.0 27-34 F

C₄₂H₄₄F₄N₁₀O₆ 861.34 862.0 27-35 F

C₄₃H₄₄F₄N₁₀O₆ 873.34 874.0 27-36 F

C₄₃H₄₆F₄N₁₀O₆ 875.35 876.0 27-37 F

C₄₂H₄₇F₄N₉O₇ 866.35 867.0 27-38 F

C₄₂H₄₉F₄N₉O₇ 868.37 869.0 27-39 F

C₄₂H₄₉F₄N₉O₆ 852.37 853.0 27-40 F

C₄₂H₄₇F₄N₉O₆ 850.36 851.0 27-41 F O(CH₂)₂OCH₃ C₄₂H₄₈F₄N₈O₈ 869.35 870.027-42 F

C₄₆H₅₃F₄N₉O₈ 936.40 937.0 27-43 F

C₄₈H₅₈F₄N₁₀O₇ 963.44 964.2 27-44 F

C₄₉H₆₀F₄N₁₀O₇ 977.46 978.2 27-45 F

C₄₈H₅₈F₄N₁₀O₈ 979.44 980.0 27-46 F

C₄₇H₅₅F₄N₉O₈ 950.41 951.0 27-47 F

C₄₆H₅₄F₄N₁₀O₇ 935.41 937.0 27-48 F

C₄₆H₅₃F₄N₉O₈ 936.4 936.0 27-49 F

C₄₇H₅₅F₄N₉O₈ 950.41 951.0 27-50 F

C₄₈H₅₈F₄N₁₀O₇ 963.44 964.0 27-51

C₄₇H₅₇F₃N₁₀O₇ 931.44 932.0 27-52

C₄₈H₅₇F₃N₁₀O₉ 975.43 976.0 27-53

C₄₂H₄₈F₃N₉O₈ 864.36 865.0 27-54

C₄₄H₅₁F₃N₈O₇ 861.38 862.0 27-55

C₄₃H₅₀F₃N₉O₈ 878.37 879.0 27-56

C₄₅H₅₄F₃N₉O₉ 922.4 923.0 27-57

C₄₃H₅₀F₃N₉O₈ 878.37 879.0 27-58

C₅₁H₆₃F₃N₁₀O₉ 1,017.47 1018.2 27-59

C₄₇H₅₆F₃N₉O₈ 932.42 933.0 27-60

C₄₇H₅₆F₃N₉O₈ 932.42 933.0 27-61 CH₂N(CH₃)₂ C₄₂H₅₀F₃N₉O₆ 834.38 834.827-62

C₄₄H₅₀F₃N₉O₆ 858.38 858.8 27-63 CH₂Oi-Pr C₄₃H₅₁F₃N₈O₇ 849.38 849.8 27-64CH(CH₃)OCH₃ C₄₂H₄₉F₃N₈O₇ 835.37 835.8 27-65 NH(CH₂)₃OCH₃ C₄₃H₅₂F₃N₉O₇864.39 864.8 27-66 Cl

C₄₂H₄₄ClF₃N₁₀O₆ 877.31 877.6 27-67 Cl NH(CH₂)₃OCH₃ C₄₂H₄₉ClF₃N₉O₇ 884.34884.6 27-68 Cl NHCH₃ C₄₀H₄₅ClF₃N₉O₆ 840.31 840.6 27-69 Cl

C₄₄H₅₀ClF₃N₈O₆ 879.35 879.6 27-70 Cl

C₄₄H₄₉ClF₃N₉O₆ 892.35 892.6 27-71 Cl

C₄₈H₅₃ClF₃N₁₁O₇ 988.38 989.6 27-72 Cl

C₄₈H₅₈ClF₃N₁₀O₇ 979.41 979.6 27-73 Cl

C₄₆H₅₄ClF₃N₁₀O₇ 951.38 951.6 27-74 Cl

C₄₈H₅₈ClF₃N₁₀O₈ 995.41 995.6 27-75 Cl

C₄₉H₆₀ClF₃N₁₀O₇ 993.43 993.5 27-76 Cl

C₄₆H₅₃ClF₃N₉O₈ 952.37 952.9

TABLE 28

Calc Found Ex No. R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 28-1 

C₄₃H₄₇F₅N₈O₆ 867.35 867.4 28-2 

C₄₃H₅₀F₃N₉O₇ 862.38 862.4 28-3 

C₄₄H₄₇F₃N₁₀O₆ 869.36 869.4 28-4 

C₄₃H₄₇F₃N₁₀O₆ 857.36 857.4 28-5  C(CH₃)₂OH C₄₃H₅₁F₃N₈O₇ 849.38 849.428-6 

C₄₃H₄₉F₃N₈O₇ 847.37 847.4 28-7 

C₄₅H₅₃F₃N₈O₇ 875.4 875.4 28-8 

C₄₆H₅₆F₃N₉O₈ 920.42 920.4 28-9 

C₄₄H₅₄F₃N₉O₆ 862.42 862.4 28-10

C₄₃H₅₂F₃N₉O₆ 848.4 848.4 28-11 NH(CH₂)₂OCH₃ C₄₃H₅₂F₃N₉O₇ 864.39 864.428-12

C₄₃H₅₀F₃N₉O₆ 846.38 846.4 28-13

C₄₄H₄₉F₃N₁₀O₆ 871.38 871.4 28-14

C₄₄H₅₁F₃N₈O₆ 845.39 845.4 28-15

C₄₄H₄₉F₃N₁₀O₆ 871.38 871.4 28-16

C₄₈H₅₈F₃N₉O₈ 946.44 946.4 28-17

C₄₉H₆₁F₃N₁₀O₇ 959.47 959.4 28-18

C₄₉H₆₁F₃N₁₀O₇ 959.47 959.4 28-19

C₄₉H₆₁F₃N₁₀O₈ 975.46 975.4 28-20

C₄₉H₅₉F₃N₁₀O₇ 957.45 957.4 28-21 O(CH₂)₂OCH₃ C₄₃H₅₁F₃N₈O₈ 865.38 865.428-22

C₄₅H₅₂F₃N₉O₆ 872.40 872.4 28-23 tBu C₄₄H₅₃F₃N₈O₆ 847.40 848.4 28-24

C₄₆H₅₄F₃N₉O₈ 918.41 918.6 28-25

C₅₀H₆₃F₃N₁₀O₇ 973.48 973.6 28-26

C₄₇H₅₇F₃N₁₀O₇ 931.44 931.6 28-27

C₄₆H₅₆F₃N₉O₆ 888.43 888.6 28-28

C₄₇H₅₈F₃N₉O₈ 934.44 934.6 28-29

C₄₅H₅₂F₃N₉O₆ 872.40 872.6 28-30

C₄₇H₅₈F₃N₉O₈ 934.44 934.6 28-31

C₄₄H₄₉F₅N₈O₆ 881.37 882.0 28-32

C₄₈H₅₈F₃N₉O₈ 946.44 947.0 28-33

C₅₂H₆₅F₃N₁₀O₉ 1,031.49 1032.2 28-34

C₄₇H₅₆F₃N₉O₈ 932.42 933.0 28-35 CH₂N(CH₃)₂ C₄₃H₅₂F₃N₉O₆ 848.4 848.828-36 Cl NHCH₃ C₄₁H₄₇ClF₃N₉O₆ 854.33 854.6 28-37 Cl NH(CH₂)₂OCH₃C₄₃H₅₁ClF₃N₉O₇ 898.36 898.6 28-38 Cl

C₄₅H₅₂ClF₃N₈O₆ 893.37 893.6 28-39 Cl

C₄₃H₄₆ClF₃N₁₀O₆ 891.32 891.6 28-40 Cl

C₄₅H₅₁ClF₃N₉O₆ 906.36 906.6 28-41 Cl

C₄₉H₆₀ClF₃N₁₀O₇ 993.43 993.4 28-42 Cl

C₄₇H₅₆ClF₃N₁₀O₇ 965.4 965.4 28-43 Cl

C₄₉H₆₀ClF₃N₁₀O₈ 1,009.42 1009.5

TABLE 29

Ex R^(11a) R^(11b) R^(7a) R^(7b) Calc Found No. R^(11c) R^(11d) R^(7c)R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 29-1  R^(7a) = CF₃

C₅₁H₆₃F₃N₁₀O₈ 1,001.48 1001.4 29-2  R^(7a) = CF₃

C₄₂H₄₇F₃N₈O₅ 801.36 801.4 29-3  R^(7a) = CF₃ NHCH₃ C₄₀H₄₆F₃N₉O₅ 790.36790.2 29-4  R^(7a) = CF₃

C₄₂H₄₅F₃N₁₀O₅ 827.35 827.2 29-5  R^(7a) = CF₃

C₄₄H₅₁F₃N₈O₅ 829.39 829.4 29-6  R^(7a) = CH₃

C₄₄H₅₄N₈O₅ 775.42 775.4 29-7  R^(7a) = OCH₂CHF₂

C₅₂H₆₆F₂N₁₀O₉ 1,013.50 1013.6 29-8  R^(11b) = CH₃

C₄₄H₅₄N₈O₅ 775.42 775.4 29-9  R^(7a) = OCH₂cPr

C₄₅H₅₂N₁₀O₆ 829.41 829.4 29-10 R^(7a) = OCH₂cPr

C₅₄H₇₀N₁₀O₉ 1,003.53 1004.0 29-11 R^(7a) = OCH₃

C₅₁H₆₆N₁₀O₉ 963.5 963.6 29-12 R^(7a) = O(CH₂)₂OCH₃

C₄₆H₅₈N₈O₇ 835.44 835.4 29-13 R^(7a) = Oi-Pr NHCH₃ C₄₂H₅₃N₉O₆ 780.41780.4 29-14 R^(11d) = CH₃ R^(7a) = OCF₃

C₄₅H₅₃F₃N₈O₆ 859.4 859.4 29-15 R^(7a) = OCH₂t-Bu

C₅₅H₇₄N₁₀O₉ 1,019.56 1019.6 29-16 R^(7a) = OcPr

C₄₆H₅₆N₈O₆ 817.43 817.4 29-17 R^(7a) = OCF₃

C₄₉H₆₀F₃N₉O₈ 960.45 960.4 29-18 R^(7a) = OCF₃

C₄₈H₅₉F₃N₁₀O₇ 945.45 945.4 29-19 R^(7a) = OCF₃

C₄₆H₅₄F₃N₉O₇ 902.41 902.4 29-2- R^(7a) = OCF₃

C₄₆H₅₄F₃N₉O₈ 918.41 918.4 29-21 R^(7a) = OCF₃

C₄₈H₅₆F₃N₉O₇ 928.43 928.4 29-22 R^(11b) = CF₃

C₅₁H₆₃F₃N₁₀O₈ 1,001.48 1001.4 29-23 R^(11b) = OCH₃

C₄₄H₅₄N₈O₆ 791.42 791.4 29-24 R^(11b) = F

C₄₃H₅₁FN₈O₅ 779.4 779.4 29-25 R^(7a) = OCH₃ R^(7c) = OCH₃

C₅₂H₆₈N₁₀O₁₀ 993.51 993.4 29-26 R^(11b) = OCF₃

C₄₄H₅₁F₃N₈O₆ 845.39 845.4 29-27 R^(11a) = CH₃

C₅₁H₆₆N₁₀O₈ 947.51 947.6 29-28 R^(7a) = OCHF₂

C₅₁H₆₄F₂N₁₀O₉ 999.48 999.4 29-29 R^(7a) = OCF₃

C₄₈H₅₇F₃N₁₀O₇ 943.44 943.4 29-30 R^(7a) = OCF₃

C₄₇H₅₆F₃N₉O₈ 932.42 932.4 29-31 R^(7a) = OCF₃

C₅₁H₆₃F₃N₁₀O₉ 1,017.47 1017.4 29-32 R^(11a) = OCF₃

C₅₁H₆₃F₃N₁₀O₉ 1,017.47 1017.4 29-33 R^(11a) = CF₃

C₅₁H₆₃F₃N₁₀O₈ 1,001.48 1001.4 29-34 R^(11d) = CH₃ R^(7a) = CH₃

C₄₅H₅₆N₈O₅ 789.44 789.4 29-35 R^(11a) = OCH₃

C₄₄H₅₄N₈O₆ 791.42 792.0 29-36 R^(7b) = F

C₅₀H₆₃FN₁₀O₈ 951.48 952.2 29-37 R^(11a) = Cl

C₄₅H₅₅ClN₁₀O₆ 867.4 867.0

TABLE 30

Ex R^(11a) R^(11b) R^(7a) R^(7b) Calc Found No. R^(11c) R^(11d) R^(7c)R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 30-1 CH((R)OH)CH₂OH C₄₁H₅₀N₈O₇767.38 767.6 30-2 R^(11b) = CH₃

C₄₅H₅₆N₈O₅ 789.44 789.4 30-3 R^(7a) = OCH₂CHF₂

C₄₄H₅₀F₂N₁₀O₆ 853.39 853.4 30-4 R^(7a) = OCH₂CHF₂

C₄₆H₅₆F₂N₈O₆ 855.43 855.4 30-5 R^(11b) = CH₃

C₅₂H₆₈N₁₀O₈ 961.52 961.6 30-6 R^(7a) = OCH₃

C₄₅H₅₆N₈O₆ 805.43 805.4 30-7 R^(7a) = CF₃

C₄₅H₅₃F₃N₈O₅ 843.41 843.4 30-8 R^(7a) = OCH₂CH₃

C₅₃H₇₀N₁₀O₉ 991.53 991.4 30-9 R^(7a) = OCF₃

C₄₅H₅₃F₃N₈O₆ 859.4 859.4

TABLE 31

Calc Found Ex No. R^(9a) R^(9b) Formula [M + H]⁺ [M + H]⁺ 31-1 (R)CH₃C₄₄H₅₁F₃N₈O₆ 845.39 845.4 31-2 (S)CH₃ C₄₄H₅₁F₃N₈O₆ 845.39 845.4 31-3(S)CH₃ C₄₄H₅₁F₃N₈O₆ 845.39 845.4

TABLE 32

Ex Calc Found No. R^(9a) R^(9b) R^(9c) R^(9d) R⁵ Formula [M + H]⁺ [M +H]⁺ 32-1  R^(9b) = (S)CH₂OCH₃

C₄₅H₅₅N₇O₆ 790.42 790.4 32-2  R^(9b) = (R)CH₃ CH₂NHC(O)CH₃ C₄₂H₅₀N₈O₆763.39 763.4 32-3  R^(9b) = (R)CH₃

C₄₃H₄₉N₉O₅ 772.39 772.4 32-4  R^(9b) = (R)CH₃

C₄₄H₅₃N₇O₅ 760.41 760.4 32-5  R^(9b) = (S)CH₃ CH₂NHC(O)CH₃ C₄₂H₄₇N₉O₅758.37 758.4 32-6  R^(9b) = (S)CH₃

C₄₄H₅₃N₇O₅ 760.41 760.4 32-7  R^(9a) = (R)CH₃ tBu C₄₃H₅₃N₇O₅ 748.41748.4 32-8  R^(9a) = (R)CH₃ NHCH₃ C₄₀H₄₈N₈O₅ 721.38 721.2 32-9  R^(9a) =(R)CH₃

C₄₄H₅₃N₇O₅ 760.41 760.4 32-10 R^(9a) = (R)CH₃

C₄₅H₅₄N₈O₆ 803.42 803.4 32-11 R^(9a) = (S)CH₃

C₄₅H₅₄N₈O₆ 803.42 803.4 32-12 R^(9a) = (S)CH₃

C₄₄H₅₃N₇O₅ 760.41 760.4 32-13 R^(9b) = (S)CH₂OCH₃

C₄₆H₅₆N₈O₇ 833.43 833.4 32-14 R^(9b) = (R)CH₂OCH₃

C₄₄H₅₁N₉O₆ 802.4 802.4 32-15 R^(9b) = (R)CH₂OCH₃ CH₂NHC(O)CH₃ C₄₃H₅₂N₈O₇793.4 793.4 32-16 R^(9a) = (S)CH₃ R^(9c) = (R)CH₃

C₄₃H₅₁N₇O₅ 746.4 746.4 32-17 R^(9a) = (R)CH₃

C₄₆H₅₆N₈O₆ 817.43 817.4 32-18 R^(9b) = (S)CH₂OH

C₄₄H₅₃N₇O₆ 776.41 776.2 32-19 R^(9b) = (S)CH₃ R^(9d) = (R)CH₃

C₄₃H₅₁N₇O₅ 746.4 746.4 32-20 R^(9b) = (S)CH₃ R^(9c) = (R)CH₃

C₄₅H₅₅N₇O₅ 774.43 774.4 32-21 R^(9a) = (R)CH₃

C₄₆H₅₆N₈O₇ 833.43 833.4 32-22 R^(9b) = (R)CH₃ R^(9c) = (S)CH₃

C₄₅H₅₅N₇O₅ 774.43 774.4 32-23 R^(9b) = (R)CH₃ R^(9c) = (S)CH₃

C₄₇H₅₈N₈O₆ 831.45 831.4

TABLE 33

Calc Found Ex No. R^(7b) R^(7c) R^(7d) R⁵ Formula [M + H]⁺ [M + H]⁺ 33-1R^(7c) = CH₃

C₅₀H₆₅N₁₁O₈ 948.5 948.4 33-2 R^(7c) = CH₃

C₄₃H₅₃N₉O₅ 776.42 776.4 33-3 R^(7c) = CF₃

C₄₃H₅₀F₃N₉O₅ 830.39 830.4 33-4 R^(7c) = CF₃

C₅₀H₆₂F₃N₁₁O₈ 1,002.47 1002.4 33-5 R^(7c) = CF₃

C₄₁H₄₄F₃N₁₁O₅ 828.35 828.4 33-6 R^(7b) = OCH₃

C₅₀H₆₅N₁₁O₉ 964.5 964.6 33-7

C₄₂H₅₁N₉O₅ 762.40 762.9 33-8

C₄₉H₆₃N₁₁O₈ 934.49 934.1

TABLE 34

Calc Found Ex No. R^(9d) R⁵ Formula [M + H]⁺ [M + H]⁺ 34-1 (S)CH₃

C₄₄H₄₈F₄N₁₀O₆ 889.37 889.6 34-2 (S)CH₃

C₄₆H₅₄F₄N₈O₆ 891.41 891.6 34-3 (S)CH₃ NHCH₃ C₄₂H₄₉F₄N₉O₆ 852.37 852.634-4

C₄₅H₅₂F₄N₈O₆ 877.39 877.6 34-5

C₄₃H₄₆F₄N₁₀O₆ 875.35 875.4 34-6 NHCH₃ C₄₁H₄₇F₄N₉O₆ 838.36 838.4Biological Assays

The hepatitis C virus has been classified into six major differentgenotypes on the basis of nucleotide sequence, and further divided intosubtypes within genotypes. Compounds of the invention demonstratedinhibition of HCV replication in one or more of the following HCVreplicon assays.

Assay 1: HCV Genotype 1b Replicon Assay

The HCV genotype 1b replicon cell line was obtained from Apath LLC(Brooklyn, N.Y.) (APC144; Huh7 cell background). This subgenomicreplicon contains the N-terminus of the HCV core protein fused to theneomycin-resistance selectable marker. The EMCV IRES lies downstream anddrives expression of humanized Renilla luciferase fused to thenon-structural proteins NS3-NS5B. This cell line was used to determinecompound potency using the luciferase activity readout as a measurementof compound inhibition of replicon levels.

Cells were grown at 37° C. in a 5% CO₂ humidified incubator in DMEM(Invitrogen) with 10% FBS (HyClone), 1×NEAA (Invitrogen), 1× Pen-Strep(Invitrogen), and 500 μg/mL G418 (Invitrogen). On day 1 of the assay,cells were plated at 10,000 cells/well in white 96-well tissue cultureplates (Costar) in 200 μL media lacking G418. Four hours later, once thecells have adhered, the media was removed and replaced with media (noG418) containing dose-responses of test compounds. Compounds wereinitially diluted in DMSO and then diluted another 200× in media tobring the final DMSO concentration down to 0.5%. The cells wereincubated with test compounds for 48 hours. At the end of the incubationperiod, media and compound were removed from the plates and theluciferase activity was determined using Promega Renilla-Glo reagents.

To analyze the data, the luciferase activity was plotted vs. thecompound concentration, and EC₅₀ values were determined from a4-parameter robust fit model with the GraphPad Prism software package(GraphPad Software, Inc., San Diego, Calif.). Results are expressed asthe negative decadic logarithm of the EC₅₀ value, pEC₅₀.

Test compounds having a higher pEC₅₀ value in this assay show greaterinhibition of HCV genotype 1b replication. Compounds of the inventiontested in this assay typically exhibited pEC₅₀ values between about 7and about 12.

Assay 2: HCV Genotype 1a Replicon Assay

The HCV genotype 1a replicon cell line was obtained from Apath LLC(APC89; Huh7.5 cell background). This subgenomic replicon contains theN-terminus of the HCV core protein fused to the neomycin-resistanceselectable marker. The EMCV IRES lies downstream and drives expressionof the non-structural proteins NS3-NS5B. Compound potencies weredetermined using the NS3-specific protease activity in lysates as ameasurement of compound inhibition of replicon levels.

Cells were grown at 37° C. in a 5% CO₂ humidified incubator in DMEM(Invitrogen) with 10% FBS (HyClone), 1×NEAA (Invitrogen), 1× Pen-Strep(Invitrogen), and 850 μg/mL G418 (Invitrogen). On day 1 of the assay,cells were plated at 15,000 cells/well in black 96-well tissue cultureplates (Costar) in 200 μL media lacking G418. Four hours later, once thecells had adhered, the media was removed and replaced with media (noG418) containing dose-responses of test compounds. Compounds wereinitially diluted in DMSO and then diluted another 200× in media tobring the final DMSO concentration down to 0.5%. The cells wereincubated with test compounds for 48 or 72 hours. At the end of theincubation period, media and compound were removed from the plates.

To determine the NS3-specific protease activity in lysates, the cellswere lysed at room temperature in 50 μL/well of 50 mM Hepes pH 7.5, 150mM NaCl, 15% Glycerol, 0.15% Triton X-100, 10 mM DTT for 20 minutes withshaking. 50 μL of an NS3/4a protease-specific FRET substrate (AnaspecRET S1 Cat#22991) was then added to the wells at a final concentrationof 15 μM. The plates were incubated at 37° C. for 20 minutes, whichcorresponds to a timepoint at which the protease activity is still inthe linear phase. Protease activity was determined by measuringfluorescence (Excitation: 340 nm; Emission: 509 nm).

To analyze the data, the fluorescence was plotted vs. the compoundconcentration, and EC50 values were determined from a 4-parameter robustfit model using GraphPad Prism software. Compounds of the inventiontested in this assay typically exhibited pEC₅₀ values between about 7and about 11.5.

Assay 3: Replicon Assays Against Resistant Mutants

To create replicon cells with resistant mutations of interest, themutation was first introduced into the parental plasmid by site-directedmutagenesis. Mutations in genotype 1b included L31V, Y93H, and theL31V/Y93H double mutant. Mutations in genotype 1a included Q30R andL31V. The replicon plasmid was then linearized and in vitro transcribedto RNA. The RNA was used to stably transfect Huh7 cells byelectroporation, and new cell lines were selected with 500 μg/mL G418.Potencies of test compounds against these mutant cell lines weredetermined as previously described above for the HCV Genotype 1b and 1areplicon assays.

Potencies of test compounds against additional mutations of interestwere determined using transient transfection assays. These mutantsincluded and genotype 1a Y93C, Y93H, M28T, Q30E, Q30K. The mutation wasfirst introduced into the parental plasmid by site-directed mutagenesis.The replicon plasmid was then linearized and in vitro transcribed toRNA. The RNA was used to transiently transfect Huh-LUNET cells (obtainedfrom ReBLikon GmbH, Schriesheim, Germany) by electroporation, and thepotencies of test compounds against the mutants were determined aspreviously described.

Assay 4: Colony Formation Assay

Colony formation assays were used to assess overall genetic barrier ofresistance of test compounds. Replicon cells were plated in tissueculture flasks and treated with various concentrations of testcompound(s) (or DMSO control) in the presence of G418 (500-850 μg/mL)for 3-4 weeks. The media was replaced with fresh media containingcompound and G418 twice per week. Cells were split as necessary. Duringthis time, many cells died, and resistant colonies emerged. The colonieswere then fixed and stained with crystal violet/methanol. Thecombination of a compound of the invention and danoprevir (an NS3protease inhibitor) was able to significantly suppress the emergence ofresistant mutants to a greater degree than either single compound alone.

Assay 5: Replicon Assays of Combinations of Agents

Combinations of a compound of the invention and another therapeuticagent were tested as described for the HCV genotype 1b and 1a repliconassays. Cells were incubated with various combinations (in acheckerboard matrix) of test compounds for 48 hours. Potencies of eithercompound alone were determined as described above, and MacSynergy IIsoftware was used to determine if the combination of test compoundsexhibited synergy vs additivity vs antagonism. The combination of acompound of the invention and danoprevir (an NS3 protease inhibitor)showed an additive antiviral effect. Similarly, the combination of acompound of the invention and interferon alpha2b showed an additiveantiviral effect.

Assay Results

All of the compounds of Examples 1 to 77 and Tables 1 to 33 were testedin one or more of the assays described above. For example, the followingresults were obtained in the HCV genotype 1b and 1a replicon assayswhere A represents a pEC₅₀ value between 7 and 8 (EC₅₀ between 100 nMand 10 nM), B represents pEC₅₀ between 8 and 9 (EC₅₀ between 1 and 10nM), C represents pEC₅₀ between and 9 and about 10, (EC₅₀ between 1 nMand 0.1 nM), and D represents pEC₅₀>10 (EC₅₀<0.1 nM).

Example Genotype Genotype No. 1b 1a  1 D B  2 D B*  3 D B*  4 D A*  5 DB  6 D A*  7 D B*  8 D B  9 D C* 10 D C* 11 D C* 12 D C 13 D D 14 D D 15D D 16 D D 17 D C 18 D C 19 D C 20 B 21 D D 22 D D 23 C 24 C 25 D D 26 DD 27 D D 28 D C 29 D D 30 D D 31 D D 32 D D 33 D D 34 D D 35 D C 36 D C37 D C 38 D D 39 D D 40 D C 41 D D 42 D C 43 D C 44 D C 45 D D 46 D C 47D C 48 D C 49 D D 50 D D 51 D D 52 D D 53 D D 54 D D 55 D D 56 D C 57 DD 58 D D 59 D D 60 D D 61 D D 62 D D 63 D D 64 D D 65 D D 66 D D 67 C 68D C 69 D C 70 C 71 D C 72 C B 73 B 74 B 75 B 76 C 77 D D 27-1 D 27-2 C27-3 C 27-4 C 27-5 D D 27-6 C 27-7 D D 27-8 D 27-9 B 27-10 D D 27-11 C27-12 D D 27-13 C 27-14 D 27-15 D D 27-16 D D 27-17 D D 27-18 D D 27-19D 27-20 D D 27-21 D D 27-22 D D 27-23 D D 27-24 C 27-25 B 27-26 C 27-27B 27-28 D D 27-29 C 27-30 D 27-31 D D 27-32 C 27-33 D D 27-34 D D 27-35C 27-36 D D 27-37 D D 27-38 D D 27-39 C 27-40 C 27-41 C 27-42 D D 27-43D D 27-44 D D 27-45 D D 27-46 D D 27-47 D D 27-48 D D 27-49 D 27-50 D D27-51 C 27-52 D D 27-53 C 27-54 C 27-55 D 27-56 C 27-57 B 27-58 D 27-59D 27-60 D 27-61 C 27-62 C 27-63 C 27-64 D 27-65 C 27-66 D 27-67 D C27-68 D D 27-69 D D 27-70 C 27-71 D 27-72 D D 27-73 D D 27-74 D 27-75 D27-76 D 28-1 D D 28-2 D D 28-3 C 28-4 D 28-5 D D 28-6 C 28-7 D 28-8 D D28-9 C 28-10 C 28-11 C 28-12 C 28-13 D 28-14 D D 28-15 D D 28-16 D D28-17 D D 28-18 D D 28-19 D D 28-20 D D 28-21 C 28-22 D D 28-23 D D28-24 D D 28-25 D D 28-26 D D 27-27 B 28-28 B 28-29 D D 28-30 B 28-31 C28-32 D 28-32 D 28-34 D 28-35 C 28-36 D D 28-37 D 28-38 D D 28-39 D D28-40 D D 28-41 D 28-42 D 28-43 D *Compounds incubated for 48 hours; allother Genotype 1a results for 72 hour incubation

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. Additionally, all publications, patents, andpatent documents cited hereinabove are incorporated by reference hereinin full, as though individually incorporated by reference.

What is claimed is:
 1. A compound of formula (I):

wherein: R¹ is selected from C₁₋₆alkyl, phenyl, C₃₋₆cycloalkyl,heteroaryl, and heterocycle; wherein C₁₋₆alkyl is optionally substitutedwith —OR^(q), wherein R^(q) is hydrogen or C₁₋₃alkyl; R² is selectedfrom hydrogen and C₁₋₆alkyl; R³ is selected from hydrogen, C₁₋₆alkyl,—C(O)OC₁₋₆alkyl,—C(O)OC₃₋₆cycloalkyl, —C(O)NR^(a)R^(b), —C(O)C₁₋₆alkyl,—C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl; wherein R^(a) and R^(b) areindependently hydrogen or C₁₋₆alkyl; R⁴ is —C(O)R⁵ or —S(O)₂R⁶; R⁵ isselected from C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,—C(R^(k)R^(d))NR^(e)R^(f), —NR^(g)R^(h), heteroaryl, heterocycle,—CH₂-heteroaryl, and phenyl; wherein C₁₋₆alkyl is optionally substitutedwith one or two substituents independently selected from —OR^(c),—S(O)₂C₁₋₃alkyl, —NHC(O)C₁₋₃alkyl, and —NHC(O)OC₁₋₃alkyl; C₁₋₆alkoxy isoptionally substituted with —OR^(d); C₃₋₆cycloalkyl is optionallysubstituted with one, two, or three substituents independently selectedfrom C₁₋₃alkyl, NR^(j)R^(m), —OR^(n), and halo; any heterocycle isoptionally substituted with one, two, or three substituentsindependently selected from C₁₋₃alkyl, halo, —C(O)OC₁₋₃alkyl,—C(O)C₁₋₆alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)NHC₁₋₆alkyl,—C(O)NHC₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl; wherein any —C(O)C₁₋₆alkylis optionally substituted with —NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e),or heterocycle, any —C(O)C₃₋₆cycloalkyl is optionally substituted withone or two C₁₋₃alkyl, and any —C(O)NHC₁₋₆alkyl is optionally substitutedwith —OR^(n) or C₃₋₆cycloalkyl; any heteroaryl is optionally substitutedwith C₁₋₆alkyl or halo; R^(c) is independently selected from hydrogen,C₁₋₆alkyl, and phenyl; R^(d) is independently hydrogen or C₁₋₆alkyl;R^(e) is independently hydrogen or C₁₋₆alkyl; R^(f) is independentlyselected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, and —C(O)C₁₋₆alkyl;R^(n) is independently hydrogen or C₁₋₃alkyl; R^(k) is independentlyselected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and—CH₂OR^(n); R^(g) is independently hydrogen or C₁₋₆alkyl; R^(h) isindependently selected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, and—S(O)₂C₁₋₃alkyl, wherein C₁₋₆alkyl is optionally substituted with—OR^(d); R^(j) is independently hydrogen or C₁₋₆alkyl; R^(m) isindependently selected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, and—C(O)C₁₋₆alkyl; R⁶ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl,and a heteroaryl ring; R⁷, R⁸, and R¹¹ are independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OR^(n), —CH₂NR^(a)R^(b), and —CN,wherein C₁₋₆alkyl and C₁₋₆alkoxy are optionally substituted with one,two, three, four, or five halo, and wherein C₁₋₆alkoxy is optionallysubstituted with —OR^(d); R⁹ is independently selected from C₁₋₆alkyl,—CH₂OR^(n), —C(O)NR^(n)R^(p), and C(O)OR^(n), wherein C₁₋₆alkyl isoptionally substituted with —S(O)₂C₁₋₃alkyl or with —SC₁₋₃alkyl; R^(p)is independently hydrogen or C₁₋₃alkyl; R¹⁰ is selected from hydrogen,halo, C₁₋₆alkyl, —C(O)OR^(c), —C(O)NR^(a)R^(b), —CH₂NR^(a)R^(b),C₃₋₆cycloalkyl, and —CN; W′, X′, Y′, and Z′ are each carbon wherein eachcarbon atom is bonded to hydrogen or to R¹¹; W, X, Y, and Z are eachcarbon wherein each carbon atom is bonded to hydrogen or to R⁷; A_(m) is—NHC(O); Q, U, and V are each carbon wherein each carbon atom is bondedto hydrogen or to R⁸, T is nitrogen; and a, b, c, and d areindependently 0, 1, or 2; or a pharmaceutically-acceptable salt orstereoisomer thereof.
 2. The compound of claim 1 wherein: R⁵ is selectedfrom C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, —C(R^(k)R^(d))NR^(e)R^(f),—NR^(g)R^(h), heteroaryl, heterocycle, —CH₂-heteroaryl, and phenyl;wherein C₁₋₆alkyl is optionally substituted with —OR^(c) or—S(O)₂C₁₋₃alkyl; C₃₋₆cycloalkyl is optionally substituted with one ortwo C₁₋₃alkyl, or with NR^(j)R^(m) or —OR^(n); any heterocycle isoptionally substituted with one or two substituents selected fromC₁₋₃alkyl, halo, —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, and—C(O)C₃₋₆cycloalkyl, wherein —C(O)C₁₋₆alkyl is optionally substitutedwith —NHC(O)OC₁₋₃alkyl, and —C(O)C₃₋₆cycloalkyl is optionallysubstituted with one or two C₁₋₃alkyl; any heteroaryl is optionallysubstituted with C₁₋₆alkyl; R^(h) is selected from hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl; R⁶ is selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, and a heteroaryl ring; and R⁷, R⁸, and R¹¹ areindependently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy, —C(O)OR^(n),—CH₂NR^(a)R^(b), and —CN, wherein C₁₋₆alkyl and C₁₋₆alkoxy areoptionally substituted with one, two, or three halo.
 3. The compound ofclaim 2 wherein: R¹ is selected from C₁₋₆alkyl, phenyl, andC₃₋₆cycloalkyl, wherein C₁₋₆alkyl is optionally substituted with—OR^(q); R³ is selected from hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl,—C(O)NR^(a)R^(b), —C(O)C₃₋₆cycloalkyl, and —S(O)₂C₁₋₃alkyl; and R¹⁰ isselected from hydrogen, halo, and C₁₋₆alkyl.
 4. The compound of claim 3wherein the compound is a compound of formula (II):

wherein R⁵ is selected from C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy,—C(R^(k)R^(d))NR^(e)R^(f), —NR^(g)R^(h), heteroaryl, heterocycle, and—CH₂-heteroaryl; wherein any heteroaryl or heterocycle has five or sixring atoms; C₃₋₆cycloalkyl is optionally substituted with one or twoC₁₋₃alkyl; any heterocycle is optionally substituted with one or twosubstituents selected from C₁₋₃alkyl, halo, —C(O)OC₁₋₃alkyl,—C(O)C₁₋₆alkyl, and —C(O)C₃₋₆cycloalkyl, wherein —C(O)C₁₋₆alkyl isoptionally substituted with —NHC(O)OC₁₋₃alkyl, and —C(O)C₃₋₆cycloakyl isoptionally substituted with one or two C₁₋₃alkyl; R^(k), R^(d), R^(e),R^(g), and R^(h) are each independently hydrogen or C₁₋₃alkyl; R^(f) isselected from hydrogen and —C(O)C₁₋₃alkyl; R⁷ is selected from halo,C₁₋₆alkyl, and C₁₋₆alkoxy wherein C₁₋₆alkyl and C₁₋₆alkoxy areoptionally substituted with one, two, or three halo; R⁹ is C₁₋₃alkyl or—CH₂OR^(n); and T is N.
 5. The compound of claim 4 wherein T is N. 6.The compound of claim 4 wherein R¹ is isopropyl; R² is hydrogen; and R³is —C(O)OCH₃.
 7. The compound of claim 4 wherein R⁵ is selected from,—O-tert-butyl, cyclopropyl, tert-butyl, —NHCH₃, 2,2-dimethylcyclopropyl,pyrimidinyl, pyrazolyl, imidazolyl, —CH₂-pyrazolyl,1-acetylpyrrolidinyl.
 8. The compound of claim 1 wherein the compound offormula (I) is a compound of formula (III):

wherein R¹ is selected from C₁₋₆alkyl, phenyl, and C₃₋₆cycloalkyl,wherein C₁₋₆alkyl is optionally substituted with —OR^(q); R³ is selectedfrom hydrogen, C₁₋₆alkyl, —C(O)OC₁₋₆alkyl, —C(O)NR^(a)R^(b),—C(O)C₃₋₆cycloallyl, and —S(O)₂C₁₋₃alkyl; R⁵ is selected from C₁₋₆alkyl,C₃₋₆cycloalkyl, C₁₋₆alkoxy, —C(R^(k)R^(d))NR^(e)R^(f), —NR^(g)R^(h),heteroaryl, heterocycle, and —CH₂-heteroaryl; wherein: any heteroaryl orheterocycle has 5 or 6 ring atoms; C₁₋₆alkyl is optionally substitutedwith one or two substituents independently selected from —OR^(c),—NHC(O)C₁₋₃alkyl, and —NHC(O)OC₁₋₃alkyl; C₁₋₆alkoxy is optionallysubstituted with —OR^(d); C₃₋₆cycloalkyl is optionally substituted withone or two substituents independently selected from C₁₋₃alkyl and halo;any heterocycle is optionally substituted with one, two, or threesubstituents independently selected from C₁₋₃alkyl, halo,—C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, —C(O)C₃₋₆cycloalkyl, —C(O)NHC₁₋₆alkyl,and —C(O)NHC₃₋₆cycloalkyl; wherein any —C(O)C₁₋₆alkyl is optionallysubstituted with —NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e), orheterocycle, any —C(O)C₃₋₆cycloalkyl is optionally substituted with oneor two C₁₋₃alkyl, and any —C(O)NHC₁₋₆alkyl is optionally substitutedwith —OR^(n) or C₃₋₆cycloalkyl; any heteroaryl is optionally substitutedwith C₁₋₃alkyl; R^(k), R^(d), R^(e), R^(g), and R^(h) are eachindependently hydrogen or C₁₋₃alkyl; R^(f) is selected from hydrogen and—C(O)C₁₋₃alkyl; R⁷ is selected from halo, C₁₋₃alkyl, and C₁₋₃alkoxywherein C₁₋₃alkyl, and C₁₋₃alkoxy are optionally substituted with one,two, or three halo; and R⁹ is C₁₋₃alkyl; a is 1 or 2; and c is 1 or 2.9. The compound of claim 8 wherein R⁵ is selected from C₃₋₄cycloalkyl,—CH₂NR^(e)R^(f), —NR^(g)R^(h), imidazolyl, pyrazolyl, pyrimidinyl, andpyrrolidinyl; wherein: C₃₋₄cycloalkyl is optionally substituted with oneor two C₁₋₃alkyl; pyrrolidinyl is substituted with methyl and asubstituent selected from —C(O)OC₁₋₃alkyl, —C(O)C₁₋₆alkyl, and—C(O)NHC₁₋₆alkyl, wherein —C(O)C₁₋₆alkyl is substituted with—NHC(O)OC₁₋₃alkyl, —OR^(n), —NR^(d)R^(e), or heterocycle.
 10. Thecompound of claim 8, wherein R⁵ is selected from—NHCH_(3,)2,2-dimethylcyclopropyl,


11. The compound of claim 8 wherein R¹ is C₁₋₆alkyl, R² is hydrogen; andR³ is —C(O)OC₁₋₆alkyl.
 12. The compound of claim 8 wherein R⁷ isselected from fluoro, chloro, —CF₃, and —OCF₃, and R⁹ is methyl.
 13. Thecompound of claim 8 wherein: R¹ is isopropyl, R² is hydrogen; and R³ is—C(O)OCH₃; R⁷ is selected from fluoro, chloro, —CF₃, and —OCF₃, and R⁹is methyl; and R⁵ is selected from —NHCH₃,2,2-dimethylcyclopropyl, and


14. The compound of claim 8 wherein the compound is selected from:

and pharmaceutically-acceptable salts thereof.
 15. The compound of claim8 wherein the compound is selected from:

and pharmaceutically-acceptable salts thereof.
 16. A pharmaceuticalcomposition comprising a compound of claim 1 and apharmaceutically-acceptable carrier.
 17. The pharmaceutical compositionof claim 16 further comprising one or more other therapeutic agentsuseful for treating hepatitis C viral infections.
 18. The pharmaceuticalcomposition of claim 17 wherein the one or more other therapeutic agentsis selected from HCV NS3 protease inhibitors, HCV NS5B nucleoside andnon-nucleoside polymerase inhibitors, interferons and pegylatedinterferons, and ribavirin and nucleoside analogs related to ribavirin.